Is ACTA1 p.Ile332= (c.996C>A) pathogenic?

ACTA1 p.Ile332= (c.996C>A) is classified Benign/Likely benign in ACTA1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-28). Common (popmax 6.25%, afr) — too common for a highly-penetrant pathogenic allele; Associated with familial restrictive cardiomyopathy.

What condition is associated with ACTA1 p.Ile332= (c.996C>A)?

ACTA1 p.Ile332= (c.996C>A) is associated with familial restrictive cardiomyopathy, congenital myopathy 2a, typical, autosomal dominant, congenital fiber-type disproportion myopathy (ClinVar).

ACTA1 p.Ile332=

Q: How common is ACTA1 p.Ile332= (c.996C>A) in the general population?

ACTA1 p.Ile332= (c.996C>A) is common (popmax 6.25%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.996C>A · rs74897770 · VCV93555

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 6.25%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

familial restrictive cardiomyopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP -3.9, phastCons 1
Overall
CADD	17.48	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.25% African / African-American · 4,686/74,950 alleles

Filtering AF 6.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.04%

Overall 0.324% 5,231/1,613,834 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	6.25%	16
Remaining individualsnot grpmax-eligible	0.398%	251
Admixed American	0.377%	266
Middle Eastern	0.298%	336
South Asian	0.0121%	8,278
European (non-Finnish)	0.00347%	28,779

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: ACTA1
Protein: p.Ile332=
Coding: c.996C>A
MANE Select: NM_001100
dbSNP: rs74897770
Type: single nucleotide variant
Location: chr1:229431637 (GRCh38)
Gene constraint: LOEUF 0.931 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.21 · 5 PDB

Full ACTA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial restrictive cardiomyopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital myopathy 2a, typical, autosomal dominant congenital fiber-type disproportion myopathy

Similar variants

ACTA1 c.617-5C>A Likely pathogenic ★★★ same condition
ACTA1 c.990+1G>T Pathogenic ★★★ same condition
ACTA1 p.Asp13Asn Likely pathogenic ★★★ same condition
ACTA1 p.Asp290His Pathogenic ★★★ same condition
ACTA1 p.Asp58Asn Likely pathogenic ★★★ same condition
ACTA1 p.Cys376Phe Likely pathogenic ★★★ same condition
ACTA1 p.Glu102Lys Likely pathogenic ★★★ same condition
ACTA1 p.Glu336Ala 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/acta1-p-ile332 (accessed [today's date]).

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