chr1-21575777-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5

The NM_000478.6(ALPL):c.1042G>A(p.Ala348Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A348D) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

ALPL
NM_000478.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6U:2

Conservation

PhyloP100: 10.0

Publications

1 publications found

Variant links:

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

ALPL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000478.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-21575778-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 4086860.Status of the report is criteria_provided_single_submitter, 1 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, 0.99

PP5

Variant 1-21575777-G-A is Pathogenic according to our data. Variant chr1-21575777-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 555880.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPL	NM_000478.6 link	c.1042G>A	p.Ala348Thr	missense_variant	Exon 10 of 12	ENST00000374840.8	NP_000469.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8 link	c.1042G>A	p.Ala348Thr	missense_variant	Exon 10 of 12	1	NM_000478.6	ENSP00000363973.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypophosphatasia

Pathogenic:3

JKU Lab, Dept of Paediatrics, Johannes Kepler University

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

This missense variant is not present in GnomAD 4.1 and affects a highly conserved amino acid in proximity of the active site domain. The variant is predicted to affect protein function (REVEL score: 0.852). Splice-prediction algorithms predict no effect on splicing. In vitro functional studies showed reduced ALP activity without dominant negative effect. This variant has been reported in the literature in individuals affected with ALPL-related conditions (PMID:32160374;PMID:38591765;PMID:38591765;PMID:10679946). The results of the functional testing and the applied ACMG criteria can be viewed at: https://alplmutationdatabase.jku.at/table/

Aug 29, 2025

Genomenon, Inc, Genomenon, Inc

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

ALPL c.1042G>A is a missense variant that changes the amino acid at residue 348 from Alanine to Threonine. This variant has been observed in at least one proband affected with hypophosphatasia (PMID:11855933;10679946). Functional studies have been reported;however, the significance of the findings remain unclear (PMID:10679946). This variant has been described as Ala331Thr 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.Ala348Thr (c.1042G>A) as a likely pathogenic variant.

Jul 16, 2025

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ALPL c.1042G>A (p.Ala348Thr) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant was absent in 251440 control chromosomes. c.1042G>A has been reported in the literature in compound heterozygous individuals affected with autosomal recessive Hypophosphatasia (Taillandier_2000, Mumm_2002, Del Angel_2020). These data indicate that the variant may be associated with disease. The variant was found impacting protein function by reducing enzymatic activity to between 25-33% compared to wild-type (Taillandier_2000, ALPL Database). The following publications have been ascertained in the context of this evaluation (PMID: 32160374, 11855933, 10679946, 37898381, 25023282, 37422472, 38591765, 11395499, 35320273, 32973344, 18328985, 10737975). ClinVar contains an entry for this variant (Variation ID: 555880). Based on the evidence outlined above, the variant was classified as likely pathogenic for autosomal dominant and autosomal recessive hypophosphatasia.

Childhood hypophosphatasia;C0268412:Infantile hypophosphatasia;C0268413:Adult hypophosphatasia

Pathogenic:1

Dec 27, 2023

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Adult hypophosphatasia

Pathogenic:1

Jun 01, 2023

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Pathogenic:1

Apr 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 348 of the ALPL protein (p.Ala348Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive hypophosphatasia (PMID: 10679946, 11855933, 32160374). This variant is also known as A331T. ClinVar contains an entry for this variant (Variation ID: 555880). 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: 10679946). For these reasons, this variant has been classified as Pathogenic.

ALPL-related disorder

Uncertain:1

Jan 11, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ALPL c.1042G>A variant is predicted to result in the amino acid substitution p.Ala348Thr. This variant in the compound heterozygous condition along with a second variant in this gene was reported in several individuals with hypophosphatasia (reported as Ala331Thr, Taillandier et al. 2000. PubMed ID: 10679946, Mumm. 2002. PubMed ID: 11855933, Table S2, Del Angel. 2020. PubMed ID: 32160374). In vitro functional studies demonstrate that this variant led to reduced enzyme activity compared to wildtype (Taillandier et al. 2000. PubMed ID: 10679946). This variant has not been reported in a large population database, indicating this variant is rare. Tis variant is interpreted as likely pathogenic.

Infantile hypophosphatasia

Uncertain:1

Jan 02, 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

0.89

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

D;.;.;D

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.65

LIST_S2

Benign

0.0

.;D;D;D

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.7

M;.;.;M

PhyloP100

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.5

D;D;D;D

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Vest4

0.97

ClinPred

0.99

GERP RS

4.9

Varity_R

0.81

gMVP

0.86

Mutation Taster

=181/119

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over