Is ALPL p.Val374Met (c.1120G>A) pathogenic?

ALPL p.Val374Met (c.1120G>A) is classified Pathogenic/Likely pathogenic in ALPL (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-08-29). AlphaMissense: likely benign (0.3285); Very rare (popmax 0.00891%, eas); Associated with adult hypophosphatasia.

What condition is associated with ALPL p.Val374Met (c.1120G>A)?

ALPL p.Val374Met (c.1120G>A) is associated with adult hypophosphatasia, hypophosphatasia, childhood hypophosphatasia (ClinVar).

How common is ALPL p.Val374Met (c.1120G>A) in the general population?

ALPL p.Val374Met (c.1120G>A) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about ALPL p.Val374Met (c.1120G>A)?

AlphaMissense predicts likely benign (score 0.3285) — an in-silico prediction, not a clinical call.

ALPL p.Val374Met

c.1120G>A · rs552831415 · VCV1455037

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.3285 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

adult hypophosphatasia

Computational evidence

Protein change
AlphaMissense	0.3285	likely benign ⚠ discordant with ClinVar
REVEL	0.838	moderately pathogenic-leaning
SaProt	LLR -10.65	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 0.26, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 24 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00891% East Asian · 4/44,878 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000496% 8/1,614,242 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,220
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	0.000254%	393,349

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.Val374Met
Coding: c.1120G>A
MANE Select: NM_000478
dbSNP: rs552831415
Type: single nucleotide variant
Location: chr1:21575855 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 374: a β-strand

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

Disease context

adult hypophosphatasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypophosphatasia childhood hypophosphatasia infantile hypophosphatasia

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-val374met (accessed [today's date]).

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