Is ACTA1 p.Tyr296= (c.888T>C) pathogenic?

ACTA1 p.Tyr296= (c.888T>C) is classified Conflicting classifications of pathogenicity in ACTA1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-15). Ultra-rare (popmax 0.0153%, nfe); Associated with congenital fiber-type disproportion myopathy.

What condition is associated with ACTA1 p.Tyr296= (c.888T>C)?

ACTA1 p.Tyr296= (c.888T>C) is associated with congenital fiber-type disproportion myopathy, congenital myopathy 2a, typical, autosomal dominant, familial restrictive cardiomyopathy (ClinVar).

How common is ACTA1 p.Tyr296= (c.888T>C) in the general population?

ACTA1 p.Tyr296= (c.888T>C) is ultra-rare (popmax 0.0153%, nfe) (gnomAD).

How is Congenital fiber-type disproportion myopathy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ACTA1 p.Tyr296=

c.888T>C · rs770931836 · VCV740066

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0153%, nfe)

Conditions

congenital fiber-type disproportion myopathy

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 0.039	GERP -5.2, phastCons 0.47
Overall
CADD	15.09	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0153% European (non-Finnish) · 180/1,180,014 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0127%

Overall 0.0112% 180/1,614,038 alleles · ultra-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: ACTA1
Protein: p.Tyr296=
Coding: c.888T>C
MANE Select: NM_001100
dbSNP: rs770931836
Type: single nucleotide variant
Location: chr1:229431823 (GRCh38)
Gene constraint: LOEUF 0.931 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.21 · 5 PDB
Residue 296: an α-helix

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

Disease context

congenital fiber-type disproportion myopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital myopathy 2a, typical, autosomal dominant familial restrictive cardiomyopathy

For Congenital fiber-type disproportion myopathy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal

Similar variants

ACTA1 p.Tyr296Cys Uncertain significance ★ ⚠ same residue
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

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-tyr296 (accessed [today's date]).

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