Is ACTC1 p.Ala333Val (c.998C>T) pathogenic?

ACTC1 p.Ala333Val (c.998C>T) is classified Conflicting classifications of pathogenicity in ACTC1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-14). AlphaMissense: likely pathogenic (0.9495); Very rare (popmax 8.47e-05%, nfe); Associated with atrial septal defect 5.

What condition is associated with ACTC1 p.Ala333Val (c.998C>T)?

ACTC1 p.Ala333Val (c.998C>T) is associated with atrial septal defect 5, hypertrophic cardiomyopathy 11, dilated cardiomyopathy 1R (ClinVar).

How common is ACTC1 p.Ala333Val (c.998C>T) in the general population?

ACTC1 p.Ala333Val (c.998C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ACTC1 p.Ala333Val (c.998C>T)?

AlphaMissense predicts likely pathogenic (score 0.9495) — an in-silico prediction, not a clinical call.

ACTC1 p.Ala333Val

c.998C>T · rs730880406 · VCV180773

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9495 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

atrial septal defect 5

Computational evidence

Protein change
AlphaMissense	0.9495	likely pathogenic
REVEL	0.919	moderately pathogenic-leaning
SaProt	LLR -13.81	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 850 bp · p 1.5e-13 · regional, not allelic
Overall
CADD	29.5	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 8.47e-05% European (non-Finnish) · 1/1,179,944 alleles

Overall 6.84e-05% 1/1,461,696 alleles · very rare

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: ACTC1
Protein: p.Ala333Val
Coding: c.998C>T
MANE Select: NM_005159
dbSNP: rs730880406
Type: single nucleotide variant
Location: chr15:34790548 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.97 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 95.47 · 16 PDB
Residue 333: a UniProt-annotated variant site (in cmh11)

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

Disease context

atrial septal defect 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypertrophic cardiomyopathy 11 dilated cardiomyopathy 1R

Similar variants

ACTC1 p.Ala333Pro Pathogenic ★ same residue
ACTC1 p.Ala333= Likely benign ★ same residue
ACTC1 p.Ala333Ser Uncertain significance ★ ⚠ same residue
ACTC1 p.Glu101Lys Pathogenic ★★★ same condition
ACTC1 p.Val56Ile Uncertain significance ★★★ ⚠ same condition
ACTC1 p.Ala297Ser Pathogenic ★★ ⚠ same condition
ACTC1 p.Gly247Asp Pathogenic/Likely pathogenic ★★ same condition
ACTC1 p.Thr128Ile Likely pathogenic ★★ 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-ala333val (accessed [today's date]).

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