Is ALPL p.Val304Met (c.910G>A) pathogenic?

ALPL p.Val304Met (c.910G>A) is classified Uncertain significance in ALPL (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-09-01). AlphaMissense: likely benign (0.1019); Very rare (popmax 0.00833%, amr); Associated with osteogenesis imperfecta.

What condition is associated with ALPL p.Val304Met (c.910G>A)?

ALPL p.Val304Met (c.910G>A) is associated with osteogenesis imperfecta, hypophosphatasia (ClinVar).

How common is ALPL p.Val304Met (c.910G>A) in the general population?

ALPL p.Val304Met (c.910G>A) is very rare (popmax 0.00833%, amr) (gnomAD).

How is Osteogenesis imperfecta inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ALPL p.Val304Met (c.910G>A)?

AlphaMissense predicts likely benign (score 0.1019) — an in-silico prediction, not a clinical call.

ALPL p.Val304Met

c.910G>A · rs745704006 · VCV1702016

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1019 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

osteogenesis imperfecta

Computational evidence

Protein change
AlphaMissense	0.1019	likely benign
REVEL	0.34	indeterminate
SaProt	LLR -7.24	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.1	GERP -3.2
Regional constraint	o/e 0.83	unconstrained · MANE · 24 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	13.41	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00833% Admixed American · 5/60,004 alleles

Filtering AF 0.00367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00329%

Overall 0.00431% 63/1,461,844 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,001
European (non-Finnish)	0.00466%	21,455
Remaining individualsnot grpmax-eligible	0.0032%	31,254
African / African-American	0.00133%	74,996

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ALPL
Protein: p.Val304Met
Coding: c.910G>A
MANE Select: NM_000478
dbSNP: rs745704006
Type: single nucleotide variant
Location: chr1:21573712 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 304: a turn

Full ALPL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

osteogenesis imperfecta — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypophosphatasia

For Osteogenesis imperfecta (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: All ages
Prevalence: 1-5 / 10 000 (Worldwide)

Similar variants

ALPL c.1190-2A>T Pathogenic ★★ same condition
ALPL c.182-1G>A Pathogenic/Likely pathogenic ★★ same condition
ALPL c.182-2A>G Pathogenic/Likely pathogenic ★★ same condition
ALPL c.297+1G>A Pathogenic/Likely pathogenic ★★ same condition
ALPL c.298-1G>A Pathogenic ★★ same condition
ALPL c.472+1G>A Pathogenic ★★ same condition
ALPL c.62-1G>C Pathogenic/Likely pathogenic ★★ same condition
ALPL c.648+1G>A Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/alpl-p-val304met (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown