Is ACSM3 p.Cys385Ser (c.1154G>C) pathogenic?

ACSM3 p.Cys385Ser (c.1154G>C) is classified Uncertain significance in ACSM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-08). AlphaMissense: ambiguous (0.5075); Very rare (popmax 0.0018%, amr).

How common is ACSM3 p.Cys385Ser (c.1154G>C) in the general population?

ACSM3 p.Cys385Ser (c.1154G>C) is very rare (popmax 0.0018%, amr) (gnomAD).

What do computational predictors say about ACSM3 p.Cys385Ser (c.1154G>C)?

AlphaMissense predicts ambiguous (score 0.5075) — an in-silico prediction, not a clinical call.

ACSM3 p.Cys385Ser

c.1154G>C · rs759253257 · VCV2324723

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5075 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0018%, amr)

Computational evidence

Protein change
AlphaMissense	0.5075	ambiguous
REVEL	0.357	indeterminate
SaProt	LLR -8.12	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 27 kb · p 0.16 · regional, not allelic
Overall
CADD	27.6	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 0.0018% Admixed American · 1/55,546 alleles

Filtering AF 0.000362% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000262%

Overall 0.000691% 11/1,592,540 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0018%	55,546
South Asian	0.00115%	87,272
European (non-Finnish)	0.000769%	130,101

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.Cys385Ser
Coding: c.1154G>C
MANE Select: NM_005622
dbSNP: rs759253257
Type: single nucleotide variant
Location: chr16:20786088 (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-cys385ser (accessed [today's date]).

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