Is ACTC1 p.Ala297Ser (c.889G>T) pathogenic?

ACTC1 p.Ala297Ser (c.889G>T) is classified Pathogenic in ACTC1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-06). AlphaMissense: likely benign (0.1689); Absent from gnomAD v4.1; Associated with ACTC1-related disorder.

What condition is associated with ACTC1 p.Ala297Ser (c.889G>T)?

ACTC1 p.Ala297Ser (c.889G>T) is associated with ACTC1-related disorder, hypertrophic cardiomyopathy 11, atrial septal defect 5 (ClinVar).

How common is ACTC1 p.Ala297Ser (c.889G>T) in the general population?

ACTC1 p.Ala297Ser (c.889G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTC1 p.Ala297Ser (c.889G>T)?

AlphaMissense predicts likely benign (score 0.1689) — an in-silico prediction, not a clinical call.

ACTC1 p.Ala297Ser

c.889G>T · rs121912675 · VCV18325

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1689 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ACTC1-related disorder

Computational evidence

Protein change
AlphaMissense	0.1689	likely benign ⚠ discordant with ClinVar
REVEL	0.66	pathogenic-leaning
SaProt	LLR -10.94	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 850 bp · p 1.5e-13 · regional, not allelic
Overall
CADD	26.1	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

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: ACTC1
Protein: p.Ala297Ser
Coding: c.889G>T
MANE Select: NM_005159
dbSNP: rs121912675
Type: single nucleotide variant
Location: chr15:34791215 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.97 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 95.47 · 16 PDB
Residue 297: a UniProt-annotated variant site (in cmh11)

Full ACTC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ACTC1-related disorder

Also linked: hypertrophic cardiomyopathy 11 atrial septal defect 5 dilated cardiomyopathy 1R

Similar variants

ACTC1 p.Ala297Gly Uncertain significance ★ ⚠ same residue
ACTC1 p.Ala297Pro Uncertain significance ★ ⚠ same residue
ACTC1 p.Ala297= Likely benign ★ same residue
ACTC1 p.Glu101Lys Pathogenic ★★★ same condition
ACTC1 p.Val56Ile Uncertain significance ★★★ ⚠ same condition
ACTC1 p.Gly247Asp Pathogenic/Likely pathogenic ★★ same condition
ACTC1 p.Thr128Ile Likely pathogenic ★★ same condition
ACTC1 c.455-6G>A Uncertain significance ★★ same condition

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/actc1-p-ala297ser (accessed [today's date]).

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