Is ACSM4 p.Pro223Ser (c.667C>T) pathogenic?

ACSM4 p.Pro223Ser (c.667C>T) is classified Uncertain significance in ACSM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-07). AlphaMissense: likely benign (0.1318); Absent from gnomAD v4.1.

How common is ACSM4 p.Pro223Ser (c.667C>T) in the general population?

ACSM4 p.Pro223Ser (c.667C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACSM4 p.Pro223Ser (c.667C>T)?

AlphaMissense predicts likely benign (score 0.1318) — an in-silico prediction, not a clinical call.

ACSM4 p.Pro223Ser

c.667C>T · rs2540427432 · VCV3140634

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1318 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1318	likely benign
REVEL	0.164	moderately benign-leaning
SaProt	LLR -9.28	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 24 kb · p 0.0095 · regional, not allelic
Overall
CADD	20.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACSM4
Protein: p.Pro223Ser
Coding: c.667C>T
MANE Select: NM_001080454
dbSNP: rs2540427432
Type: single nucleotide variant
Location: chr12:7317183 (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.Pro223Gln Uncertain significance ★ ⚠ same residue
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

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-pro223ser (accessed [today's date]).

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