rs1800546

Positions:

• chr9-101427574-C-G
• chr9-101427574-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_Strong BP4

The NM_000035.4(ALDOB):​c.448G>C​(p.Ala150Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00439 in 1,614,172 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (16 hom.)
• Consequence: ALDOB NM_000035.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:39 O:2
• Conservation: PhyloP100: 4.33

Genes affected

ALDOB (HGNC:417): (aldolase, fructose-bisphosphate B) Fructose-1,6-bisphosphate aldolase (EC 4.1.2.13) is a tetrameric glycolytic enzyme that catalyzes the reversible conversion of fructose-1,6-bisphosphate to glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. Vertebrates have 3 aldolase isozymes which are distinguished by their electrophoretic and catalytic properties. Differences indicate that aldolases A, B, and C are distinct proteins, the products of a family of related 'housekeeping' genes exhibiting developmentally regulated expression of the different isozymes. The developing embryo produces aldolase A, which is produced in even greater amounts in adult muscle where it can be as much as 5% of total cellular protein. In adult liver, kidney and intestine, aldolase A expression is repressed and aldolase B is produced. In brain and other nervous tissue, aldolase A and C are expressed about equally. There is a high degree of homology between aldolase A and C. Defects in ALDOB cause hereditary fructose intolerance. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PP5: Variant 9-101427574-C-G is Pathogenic according to our data. Variant chr9-101427574-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-101427574-C-G is described in Lovd as [Pathogenic]. Variant chr9-101427574-C-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.021924257). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDOB	NM_000035.4	c.448G>C	p.Ala150Pro	missense_variant	5/9	ENST00000647789.2	NP_000026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDOB	ENST00000647789.2	c.448G>C	p.Ala150Pro	missense_variant	5/9		NM_000035.4	ENSP00000497767	P1

Frequencies

GnomAD3 genomes AF: 0.00313 AC: 476 AN: 152170 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00415

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00534

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00295 AC: 742 AN: 251126 Hom.: 0 AF XY: 0.00299 AC XY: 406 AN XY: 135730

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00208

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00435

Gnomad NFE exome AF: 0.00469

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00452 AC: 6611 AN: 1461884 Hom.: 16 Cov.: 32 AF XY: 0.00434 AC XY: 3159 AN XY: 727246

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.00195

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000348

Gnomad4 FIN exome AF: 0.00479

Gnomad4 NFE exome AF: 0.00530

Gnomad4 OTH exome AF: 0.00427

GnomAD4 genome AF: 0.00313 AC: 476 AN: 152288 Hom.: 2 Cov.: 32 AF XY: 0.00310 AC XY: 231 AN XY: 74474

Gnomad4 AFR AF: 0.000938

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00415

Gnomad4 NFE AF: 0.00534

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00398 Hom.: 0

Bravo AF: 0.00255

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.00270 AC: 328

EpiCase AF: 0.00447

EpiControl AF: 0.00433

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:39 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary fructosuria Pathogenic:26 Other:2

Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This variant (also referred to as p.Ala149Pro in the literature) has been previously reported in the homozygous or compound heterozygous state in individuals with hereditary fructose intolerance (PMID: 3383242, 8096362, 19768653, 15880727, 18541450, 27797444). The c.448G>C (p.Ala150Pro) variant is the most common pathogenic variant in ALDOB (PMID: 15733923). Functional studies show this variant reduces substrate affinity as well as enzyme thermal stability, quaternary structure, and activity (PMID:12417303, 12464284, 15733923). The c.448G>C (p.Ala150Pro) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.3% (874/282528) and is absent in the homozygous state. It is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.448G>C (p.Ala150Pro) variant is classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2008	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	HFI Laboratory at Boston University, Boston University	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Mar 31, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hereditary fructose intolerance (MIM#229600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to proline. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (472 heterozygotes, 2 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated glycolytic domain (NCBI, PDB). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic and likely pathogenic, and is one of the most common deleterious variants in this gene (ClinVar, PMID: 15880727). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro assays demonstrate that this missense variant results in the complete loss of catalytic activity and efficiency of substrates fructose-1,6-bisphosphate and fructose-1-phosphate (PMID: 12417303). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jul 16, 2021	PS3, PP1, PP3, PM2, PM3 -
Pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Pathogenic, for Fructose intolerance, hereditary, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PMID:18541450) (PMID:15880727) (PMID:16406649). PS4-Moderate => Recurrent mutation, found in various HFI patients from unrelated pedigrees. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect. Severe reduction of aldolase activity towards fructose-1-phosphate (F-1-P) and fructose-1,6-bisphosphate (F-1,6-P2) measured in hepatic biopsies. In vitro expression studies confirm that the recombinant enzyme has defective activity (PMID:12417303) (PMID:12205126). PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:3383242). -
Pathogenic, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 17, 2018	The ALDOB c.448G>C (p.Ala150Pro) variant is well-documented as one of the most common variants among patients with hereditary fructose intolerance in European and North American populations (Baker et al. 2015). Across a small selection of the available literature, the p.Ala150Pro variant was identified in a homozygous state in 44 patients, in a compound heterozygous state in 33 patients, and in a heterozygous state in three unaffected family members of a patient (Cross et al. 1988; Coffee et al. 2010). Control data are not reported in these studies for this variant, which is found at a frequency of 0.00895 in the European population from the 1000 Genomes Project. The ALDOB p.Ala150Pro variant protein, extracted from liver and intestinal tissues from a homozygous patient, showed a profound reduction in substrate affinity and specific activity when compared with control subjects (Cox et al. 1983), and in vitro functional studies of ALDOB variants demonstrated that the p.Ala150Pro variant protein was highly unstable with no detectable residual enzyme activity (Esposito et al. 2002). Based on the collective evidence, the p.Ala150Pro variant is classified as pathogenic for hereditary fructose intolerance. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, no assertion criteria provided	literature only	ATS em Genética Clínica, Universidade Federal do Rio Grande do Sul	Mar 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 150 of the ALDOB protein (p.Ala150Pro). This variant is present in population databases (rs1800546, gnomAD 0.5%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with inherited fructose intolerance (PMID: 3383242, 8096362, 15880727, 18541450, 19768653, 27797444). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 464). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ALDOB function (PMID: 12417303, 12464284). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Elsea Laboratory, Baylor College of Medicine	Apr 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 20, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 30, 2022	The p.Ala150Pro variant in ALDOB (frequently referred to as p.Ala149Pro) is the most common hereditary fructose intolerance (HFI) allele, accounting for approximately half of HFI alleles identified worldwide (Cross and Cox 1989 PMID: 3383242, Malay 2005 PMID: 15733923). In vitro functional studies also provide evidence that the p.Ala150Pro variant impacts protein function (Esposito 2002 PMID: 12417303, Malay 2002 PMID: 12464284, Malay 2005 PMID: 15733923). This variant has been identified in 0.47% (604/126366) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1800546). Although it has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In summary, this variant meets criteria to be classified as pathogenic for HFI in an autosomal recessive manner based upon functional evidence and biallelic occurrence in affected individuals. ACMG/AMP Criteria applied: PM3_Very Strong, PS4_Moderate, PS3_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Apr 30, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Provincial Medical Genetics Program of British Columbia, University of British Columbia	Jan 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	The ALDOB c.448G>C; p.Ala150Pro variant, also reported as Ala149Pro (rs1800546; ClinVar Variation ID: 464), is one of the most common pathogenic ALDOB variants and has been identified in numerous affected individuals both as a homozygote and in trans with other pathogenic ALDOB variants (Cross 1988, Davit-Spraul 2008, Ferri 2012, Li 2018, Valadares 2015). This variant is found in the general population with an overall allele frequency of 0.3% (874/282,528 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.701). Functional studies demonstrate that this variant causes protein instability and loss of enzymatic activity (Esposito 2002, Malay 2002, Malay 2005). Based on the available information, the p.Ala150Pro variant is considered to be pathogenic. References: Cross NC et al. Catalytic deficiency of human aldolase B in hereditary fructose intolerance caused by a common missense mutation. Cell. 1988;53(6):881-885. PMID: 3383242. Davit-Spraul A et al. Hereditary fructose intolerance: frequency and spectrum mutations of the aldolase B gene in a large patients cohort from France--identification of eight new mutations. Mol Genet Metab. 2008;94(4):443-447. PMID: 18541450. Esposito G et al. Structural and functional analysis of aldolase B mutants related to hereditary fructose intolerance. FEBS Lett. 2002;531(2):152-156. PMID: 12417303. Ferri L et al. Integration of PCR-Sequencing Analysis with Multiplex Ligation-Dependent Probe Amplification for Diagnosis of Hereditary Fructose Intolerance. JIMD Rep. 2012;6:31-37. PMID: 23430936 Li H et al. Acute liver failure in neonates with undiagnosed hereditary fructose intolerance due to exposure from widely available infant formulas. Mol Genet Metab. 2018;123(4):428-432. PMID: 29510902. Malay AD et al. Structure of the thermolabile mutant aldolase B, A149P: molecular basis of hereditary fructose intolerance. J Mol Biol. 2005;347(1):135-144. PMID: 15733923. Malay AD et al. The temperature dependence of activity and structure for the most prevalent mutant aldolase B associated with hereditary fructose intolerance. Arch Biochem Biophys. 2002;408(2):295-304. PMID: 12464284. Valadares ER et al. Hereditary fructose intolerance in Brazilian patients. Mol Genet Metab Rep. 2015;4:35-38. PMID: 26937407. -
not provided, no classification provided	literature only	GeneReviews	-	One of the six most common HFI variants in US and European populations including Turkey, Spain, Central Europe, France, US, and Italy -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	May 02, 2023	PS3, PM2, PP2, PP3, PP4, PP5 -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 21, 2017	Variant summary: The ALDOB c.448G>C (p.Ala150Pro) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 328/121396 control chromosomes at a frequency of 0.0027019, which does not exceed the estimated maximal expected allele frequency of a pathogenic ALDOB variant (0.0044721). The variant of interest has been reported in multiple affected individuals via publications. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 12, 2019	NM_000035.3(ALDOB):c.448G>C(A150P) is classified as pathogenic in the context of hereditary fructose intolerance. Sources cited for classification include the following: PMID 23114028, 11757579, 16406649, 15880727, 18541450, 3383242, 1967768, and 15532022. Classification of NM_000035.3(ALDOB):c.448G>C(A150P) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Jan 29, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -

not provided Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 02, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2022	Reported as the most common ALDOB pathogenic variant among individuals of European ancestry (Santer et al., 2005); Published functional studies demonstrate A150P decreases substrate affinity and enzyme stability and results in loss of thermostability and significantly lower activity than wild type protein (Esposito et al., 2002; Malay et al., 2002); X-ray crystallography shows extensive structural perturbation at the site of the substitution and in the adjacent loop regions (Malay et al., 2005); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12464284, 15733923, 19768653, 29510902, 27797444, 15880727, 12417303, 3383242, 25333069, 22975760, 18541450, 26937407, 29984853, 31589614, 30609409, 22773061, 31980526, 8096362, 34440436, 34426522) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ALDOB: PM3:Very Strong, PS3, PM2:Supporting, PP1 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 17, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 27, 2019	DNA sequence analysis of the ALDOB gene demonstrated a sequence change, c.448G>C, in exon 5 that results in an amino acid change, p.Ala150Pro. This sequence change has been described in the gnomAD database with a population frequency of 0.49%, however, it has not been observed in homozygous state in any individuals (dbSNP rs1800546). This sequence change (alternatively reported as p.Ala149Pro) has previously been described in the homozygous or compound heterozygous states with another pathogenic variant, in individuals with hereditary fructose intolerance (PMID: 3383242, PMID: 27797444, PMID: 22975760, PMID: 26937407, PMID: 20162364) and is one of the most commonly reported ALDOB pathogenic variant in individuals of European ancestry. The p.Ala150Pro change affects a moderately conserved amino acid residue located in a domain of the ALDOB protein that is known to be functional. In vitro functional analyses showed that the p.Ala150Pro substitution has an impact on both substrate affinity and enzyme stability and wild type protein activity is reduced (PMID: 12417303, PMID: 12464284). -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 21, 2022	PP4, PS3, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jun 27, 2023	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 24, 2021

The c.448G>C (p.A150P) alteration is located in exon 5 (coding exon 4) of the ALDOB gene. This alteration results from a G to C substitution at nucleotide position 448, causing the alanine (A) at amino acid position 150 to be replaced by a proline (P). Based on data from gnomAD, the C allele has an overall frequency of 0.31% (874/282528) total alleles studied. The highest observed frequency was 0.49% (627/128866) of European (non-Finnish) alleles. This mutation (also referred to as A149P) has been reported in the homozygous and compound heterozygous states in many affected patients, and is the most frequent ALDOB mutation with a frequency of up to 64% in various cohorts of patients with hereditary fructose intolerance (Cross, 1988; Santer, 2005; Davit-Spraul, 2008; Coffee, 2010). This amino acid position is not well conserved in available vertebrate species. In vitro functional studies show that protein with the p.A150P mutation demonstrates temperature-dependent structural changes and decreased enzyme activity compared to wild type protein (Esposito, 2002; Malay, 2002). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Mar 28, 2022

ACMG classification criteria: PS3, PM3, PP3 -

ALDOB-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 26, 2024

The ALDOB c.448G>C variant is predicted to result in the amino acid substitution p.Ala150Pro. This variant, also referred to as p.Ala149Pro in the literature, is one of the most frequently reported causative variants for hereditary fructose intolerance (Cross et al. 1988. PubMed ID: 3383242; Sánchez-Gutiérrez et al. 2002. PubMed ID: 12205126). This variant is reported in 0.49% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;D;D;T;D;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	.;.;.;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.022	T;T;T;T;T;T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	3.2	M;M;M;.;M;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.8	D;.;.;.;.;.
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0040	D;.;.;.;.;.
Sift4G	Uncertain	0.013	D;.;.;D;.;.
Polyphen		1.0	D;D;D;.;D;.
Vest4		0.96
MVP		0.93
MPC		0.13
ClinPred		0.045	T
GERP RS		6.2
Varity_R		0.94
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1800546; hg19: chr9-104189856;