rs786204617

Variant names:

• chr1-21568122-C-T
• rs766076920
• NM_000478.6:c.667C>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.667C>T​(p.Arg223Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,798 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. R223Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ALPL NM_000478.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 1.79
• Publications: 6 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 20 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000478.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-21568123-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 381586.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, 0.991
• PP5: Variant 1-21568122-C-T is Pathogenic according to our data. Variant chr1-21568122-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 189001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000478.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPL	NM_000478.6	MANE Select	c.667C>T	p.Arg223Trp	missense	Exon 7 of 12	NP_000469.3
	ALPL	NM_001369803.2		c.667C>T	p.Arg223Trp	missense	Exon 7 of 12	NP_001356732.1
	ALPL	NM_001369804.2		c.667C>T	p.Arg223Trp	missense	Exon 7 of 12	NP_001356733.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPL	ENST00000374840.8	TSL:1 MANE Select	c.667C>T	p.Arg223Trp	missense	Exon 7 of 12	ENSP00000363973.3
	ALPL	ENST00000374832.5	TSL:2	c.667C>T	p.Arg223Trp	missense	Exon 7 of 12	ENSP00000363965.1
	ALPL	ENST00000540617.5	TSL:2	c.502C>T	p.Arg168Trp	missense	Exon 6 of 11	ENSP00000442672.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151934 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251478 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461864 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

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

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151934 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74184

African (AFR) AF: 0.00 AC: 0 AN: 41328

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypophosphatasia Pathogenic:4

Dec 22, 2023

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.667C>T (p.Arg223Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251478 control chromosomes (gnomAD). c.667C>T (also known as R206W) has been reported in the literature in multiple bi-allelic individuals affected with Hypophosphatasia (example: Mornet_1998, Brun-Heath_2005, Collman_2009, Orimo_2009, Hofmann_2013, McKiernan_2017, DelAngel_2020), however some of these individual had variants classified as VUS or likely benign in trans (Orimo_2009, Brun-Heath_2005). Multiple publications have reported experimental evidence evaluating an impact on protein function. All of these studies have shown variant effect results in <10% of normal activity (example: Hofmann_2013, Orimo_2009, Brun-Heath_2005). The following publications have been ascertained in the context of this evaluation (PMID: 23454488, 11760847, 18769927, 9781036, 28401263, 15694177, 32160374). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Mar 05, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 23454488) - PS3_moderate.The c.667C>T;p.(Arg223Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 189001; PMID: 24100244; PMID: 23454488; PMID: 20383509) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Alk-phosphatase) - PM1. The variant is present at low allele frequencies population databases (rs766076920 – gnomAD 0.0001061%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg223Trp) was detected in trans with a pathogenic variant (PMID: 24100244; PMID: 23454488; PMID: 20383509) - PM3. Pathogenic missense variant in this residue have been reported (ClinVar ID: 381586) - PM5. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. The variant was identified in an individual with a highly specific phenotype for the condition -PP4. In summary, the currently available evidence indicates that the variant is pathogenic.

Aug 29, 2025

Genomenon, Inc, Genomenon, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

ALPL c.667C>T is a missense variant that changes the amino acid at residue 223 from Arginine to Tryptophan. This variant has been observed in at least one proband affected with hypophosphatasia (PMID:32811521;34673643;11760847;11855933;23454488;15694177). The variant was found to segregate with disease in at least one affected family (PMID:23454488). At least one functional study has demonstrated a substantial alteration in protein function relative to the wild-type (PMID:23454488;11760847;12162492;1 2499779;11760847). This variant has been described as Arg206Trp in the literature. 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.Arg223Trp (c.667C>T) as a pathogenic variant.

May 18, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Infantile hypophosphatasia Pathogenic:1

Oct 09, 2014

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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.

Adult hypophosphatasia Pathogenic:1

Feb 19, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:1

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 223 of the ALPL protein (p.Arg223Trp). This variant is present in population databases (rs766076920, gnomAD 0.003%). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 11760847, 23454488, 24100244). This variant is also known as p.Arg206Trp. ClinVar contains an entry for this variant (Variation ID: 189001). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 11760847, 23454488). This variant disrupts the p.Arg223 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11855933, 15694177, 23509830, 24100244). 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		1.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.94		Gain of catalytic residue at M226 (P = 0.0045)
MVP		0.98
MPC		1.3
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.90
gMVP		0.97
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs766076920; hg19: chr1-21894615; COSMIC: COSV66376963; COSMIC: COSV66376963;