Is ACSM3 p.Val503Ala (c.1508T>C) pathogenic?

ACSM3 p.Val503Ala (c.1508T>C) is classified Uncertain significance in ACSM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-07). AlphaMissense: likely pathogenic (0.6951); Very rare (popmax 0.00186%, nfe).

How common is ACSM3 p.Val503Ala (c.1508T>C) in the general population?

ACSM3 p.Val503Ala (c.1508T>C) is very rare (popmax 0.00186%, nfe) (gnomAD).

What do computational predictors say about ACSM3 p.Val503Ala (c.1508T>C)?

AlphaMissense predicts likely pathogenic (score 0.6951) — an in-silico prediction, not a clinical call.

ACSM3 p.Val503Ala

c.1508T>C · VCV3825419

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6951 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00186%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6951	likely pathogenic
REVEL	0.666	pathogenic-leaning
SaProt	LLR -9.20	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 27 kb · p 0.16 · regional, not allelic
Overall
CADD	26.4	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 0.00186% European (non-Finnish) · 22/1,179,980 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00143% 23/1,614,026 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00186%	53,635
African / African-American	0.00133%	74,932

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: ACSM3
Protein: p.Val503Ala
Coding: c.1508T>C
MANE Select: NM_005622
Type: single nucleotide variant
Location: chr16:20792289 (GRCh38)
Gene constraint: LOEUF 0.999 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.12

Full ACSM3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACSM3 p.Pro291Leu Uncertain significance ★★ ⚠ same type
THUMPD1 p.Arg157Ter Pathogenic ★ same type
THUMPD1 p.Gln44Ter Likely pathogenic ★ same type
THUMPD1 p.Leu114Ter Pathogenic ★ same type
THUMPD1 p.Pro164Ser Pathogenic ★ same type
ACSM3 p.Ala139Thr Uncertain significance ★ ⚠ same type
ACSM3 p.Ala183Thr Uncertain significance ★ ⚠ same type
ACSM3 p.Ala215Val Uncertain significance ★ ⚠ same type

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/acsm3-p-val503ala (accessed [today's date]).

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