1-21577448-G-T

Variant names:

• chr1-21577448-G-T
• rs1054159992
• NM_000478.6:c.1375G>T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000478.6(ALPL):​c.1375G>T​(p.Val459Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,459,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V459A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: ALPL NM_000478.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 9.49
• Publications: 2 publications found

Genes affected

ALPL (HGNC:438): (alkaline phosphatase, biomineralization associated) This gene encodes a member of the alkaline phosphatase family of proteins. There are at least four distinct but related alkaline phosphatases: intestinal, placental, placental-like, and liver/bone/kidney (tissue non-specific). The first three are located together on chromosome 2, while the tissue non-specific form is located on chromosome 1. The product of this gene is a membrane bound glycosylated enzyme that is not expressed in any particular tissue and is, therefore, referred to as the tissue-nonspecific form of the enzyme. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature enzyme. This enzyme may play a role in bone mineralization. Mutations in this gene have been linked to hypophosphatasia, a disorder that is characterized by hypercalcemia and skeletal defects. [provided by RefSeq, Oct 2015]

ALPL Gene-Disease associations (from GenCC):

• adult hypophosphatasia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet
• childhood hypophosphatasia

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, ClinGen, Orphanet
• hypophosphatasia

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, G2P
• infantile hypophosphatasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia
• odontohypophosphatasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• perinatal lethal hypophosphatasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000478.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-21577448-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 554044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 220 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 1.2672 (below the threshold of 3.09). Trascript score misZ: 1.9021 (below the threshold of 3.09). GenCC associations: The gene is linked to adult hypophosphatasia, infantile hypophosphatasia, odontohypophosphatasia, childhood hypophosphatasia, hypophosphatasia, perinatal lethal hypophosphatasia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 1-21577448-G-T is Pathogenic according to our data. Variant chr1-21577448-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 558598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPL	NM_000478.6	c.1375G>T	p.Val459Leu	missense_variant	Exon 12 of 12	ENST00000374840.8	NP_000469.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8	c.1375G>T	p.Val459Leu	missense_variant	Exon 12 of 12	1	NM_000478.6	ENSP00000363973.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1459570 Hom.: 0 Cov.: 33 AF XY: 0.0000151 AC XY: 11 AN XY: 726266

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51268

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111924

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypophosphatasia Pathogenic:2

Apr 24, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ALPL c.1375G>T (p.Val459Leu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 244600 control chromosomes. c.1375G>T has been observed in at-least one heterozygous individual with odontohypophosphatasia and at-least one compound heterozygous individual with perinatal lethal Hypophosphatasia who carried a pathogenic variant in trans (example: Fauvert_2009, Del Angel_2020). These data indicate that the variant is associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.1375G>A, p.Val459Met), supporting the critical relevance of codon 459 to ALPL protein function. At least one publication reports experimental evidence evaluating an impact on protein function. Specifically, measurement of in vitro alkaline phosphatase activity in COS-7 cells transfected with mutated cDNA with the variant of interest demonstrated a 0% (% wild type) residual alkaline phosphatase activity level (example: Fauvert_2009). The following publications have been ascertained in the context of this evaluation (PMID: 32160374, 19500388, 32973344). ClinVar contains an entry for this variant (Variation ID: 558598). Based on the evidence outlined above, the variant was classified as as pathogenic for AD and AR Hypophosphatasia.

Aug 29, 2025

Genomenon, Inc, Genomenon, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

ALPL c.1375G>T is a missense variant that changes the amino acid at residue 459 from Valine to Leucine. This variant has been observed in at least one proband affected with hypophosphatasia (PMID:19500388;32160374). At least one functional study has demonstrated a substantial alteration in protein function relative to the wild-type (PMID:19500388). It is absent or not present at a significant frequency in gnomAD. In silico models agree that this variant is possibly or probably damaging. In conclusion, we classify ALPL p.Val459Leu (c.1375G>T) as a pathogenic variant.

not provided Pathogenic:1

Jan 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 459 of the ALPL protein (p.Val459Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant hypophosphatasia and/or hypophosphatasia (PMID: 19500388; Invitae). ClinVar contains an entry for this variant (Variation ID: 558598). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ALPL protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ALPL function (PMID: 19500388). This variant disrupts the p.Val459 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11438998, 27699270, 31707452). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Infantile hypophosphatasia Uncertain:1

May 31, 2018

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;.;D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.0	.;D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	2.9	M;.;.;M
PhyloP100		9.5
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.6	D;D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.017	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Vest4		0.89
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.69
gMVP		0.95
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs1054159992; hg19: chr1-21903941; COSMIC: COSV66376347;