Is ACSM4 p.Pro321Thr (c.961C>A) pathogenic?

ACSM4 p.Pro321Thr (c.961C>A) is classified Uncertain significance in ACSM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-01). AlphaMissense: ambiguous (0.4798); Ultra-rare (popmax 0.0143%, nfe).

How common is ACSM4 p.Pro321Thr (c.961C>A) in the general population?

ACSM4 p.Pro321Thr (c.961C>A) is ultra-rare (popmax 0.0143%, nfe) (gnomAD).

What do computational predictors say about ACSM4 p.Pro321Thr (c.961C>A)?

AlphaMissense predicts ambiguous (score 0.4798) — an in-silico prediction, not a clinical call.

ACSM4 p.Pro321Thr

c.961C>A · rs754718328 · VCV2409250

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4798 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0143%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4798	ambiguous
REVEL	0.48	indeterminate
SaProt	LLR -12.75	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 24 kb · p 0.0095 · regional, not allelic
Overall
CADD	23.9	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 0.0143% European (non-Finnish) · 169/1,179,780 alleles

Filtering AF 0.0125% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0119%

Overall 0.0111% 179/1,613,632 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0143%	6,981
Remaining individualsnot grpmax-eligible	0.0128%	7,807
African / African-American	0.00267%	37,447

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.Pro321Thr
Coding: c.961C>A
MANE Select: NM_001080454
dbSNP: rs754718328
Type: single nucleotide variant
Location: chr12:7320764 (GRCh38)
Gene constraint: LOEUF 1.072 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.38

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

Similar variants

ACSM4 p.Ala101Thr Uncertain significance ★ ⚠ same type
ACSM4 p.Ala118Val Uncertain significance ★ ⚠ same type
ACSM4 p.Ala150Val Uncertain significance ★ ⚠ same type
ACSM4 p.Ala40Val Uncertain significance ★ ⚠ same type
ACSM4 p.Arg136Gln Uncertain significance ★ ⚠ same type
ACSM4 p.Arg156Gln Uncertain significance ★ ⚠ same type
ACSM4 p.Arg21Gln Uncertain significance ★ ⚠ same type
ACSM4 p.Arg22Cys 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/acsm4-p-pro321thr (accessed [today's date]).

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