Is ALPL p.Val474Ile (c.1420G>A) pathogenic?

ALPL p.Val474Ile (c.1420G>A) is classified Uncertain significance in ALPL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-28). AlphaMissense: likely benign (0.1102); Very rare (popmax 0.00333%, amr); Associated with adult hypophosphatasia.

What condition is associated with ALPL p.Val474Ile (c.1420G>A)?

ALPL p.Val474Ile (c.1420G>A) is associated with adult hypophosphatasia (ClinVar).

How common is ALPL p.Val474Ile (c.1420G>A) in the general population?

ALPL p.Val474Ile (c.1420G>A) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about ALPL p.Val474Ile (c.1420G>A)?

AlphaMissense predicts likely benign (score 0.1102) — an in-silico prediction, not a clinical call.

ALPL p.Val474Ile

c.1420G>A · rs376354718 · VCV1709745

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1102 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

adult hypophosphatasia

Computational evidence

Protein change
AlphaMissense	0.1102	likely benign
REVEL	0.616	indeterminate
SaProt	LLR -10.92	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.68, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 24 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	23.3	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 0.00333% Admixed American · 2/59,994 alleles

Filtering AF 0.002% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00176%

Overall 0.00236% 38/1,609,214 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,997
Remaining individualsnot grpmax-eligible	0.0032%	31,221
European (non-Finnish)	0.0028%	35,755
African / African-American	0.00133%	74,934

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.Val474Ile
Coding: c.1420G>A
MANE Select: NM_000478
dbSNP: rs376354718
Type: single nucleotide variant
Location: chr1:21577493 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 474: 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

Similar variants

ALPL p.Val474Ala Uncertain significance ★ ⚠ same residue
ALPL p.Val474= Likely benign ★ same residue
ALPL c.1190-2A>T Pathogenic ★★ same condition
ALPL c.298-1G>A Pathogenic ★★ same condition
ALPL c.62-1G>C Pathogenic/Likely pathogenic ★★ same condition
ALPL c.648+1G>A Pathogenic ★★ same condition
ALPL c.648+1G>T Pathogenic ★★ same condition
ALPL c.649-1G>A Pathogenic/Likely 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-val474ile (accessed [today's date]).

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