Is ACSM4 p.Val487Met (c.1459G>A) pathogenic?

ACSM4 p.Val487Met (c.1459G>A) is classified Uncertain significance in ACSM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-03). AlphaMissense: likely pathogenic (0.7589); Very rare (popmax 0.00133%, afr).

How common is ACSM4 p.Val487Met (c.1459G>A) in the general population?

ACSM4 p.Val487Met (c.1459G>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ACSM4 p.Val487Met (c.1459G>A)?

AlphaMissense predicts likely pathogenic (score 0.7589) — an in-silico prediction, not a clinical call.

ACSM4 p.Val487Met

c.1459G>A · VCV3825460

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7589 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7589	likely pathogenic
REVEL	0.307	indeterminate
SaProt	LLR -12.07	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 5.1	GERP 1, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 24 kb · p 0.0095 · regional, not allelic
Overall
CADD	26.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00133% African / African-American · 1/75,042 alleles

Overall 6.84e-05% 1/1,461,670 alleles · very rare

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: ACSM4
Protein: p.Val487Met
Coding: c.1459G>A
MANE Select: NM_174941 · reported on NM_001080454
Type: single nucleotide variant
Location: chr12:7324521 (GRCh38)

Full ACSM4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/acsm4-p-val487met (accessed [today's date]).

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