Is ACTA1 p.Lys375= (c.1125A>G) pathogenic?

ACTA1 p.Lys375= (c.1125A>G) is classified Conflicting classifications of pathogenicity in ACTA1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-14). Rare (popmax 0.153%, afr); Associated with familial restrictive cardiomyopathy.

What condition is associated with ACTA1 p.Lys375= (c.1125A>G)?

ACTA1 p.Lys375= (c.1125A>G) is associated with familial restrictive cardiomyopathy, congenital myopathy 2a, typical, autosomal dominant, congenital fiber-type disproportion myopathy (ClinVar).

How common is ACTA1 p.Lys375= (c.1125A>G) in the general population?

ACTA1 p.Lys375= (c.1125A>G) is rare (popmax 0.153%, afr) (gnomAD).

ACTA1 p.Lys375=

c.1125A>G · rs142311664 · VCV464116

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.153%, afr)

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 0.42	GERP -0.81, phastCons 1
Overall
CADD	17.06	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.153% African / African-American · 115/74,942 alleles

Filtering AF 0.131% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.122%

Overall 0.00806% 130/1,613,076 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.153%	652
Remaining individualsnot grpmax-eligible	0.0128%	7,803
Admixed American	0.00333%	30,001
European (non-Finnish)	0.000424%	236,001

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.Lys375=
Coding: c.1125A>G
MANE Select: NM_001100
dbSNP: rs142311664
Type: single nucleotide variant
Location: chr1:229431508 (GRCh38)
Gene constraint: LOEUF 0.931 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.21 · 5 PDB
Residue 375: a UniProt-annotated variant site (in cmyo2a)

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 p.Lys375Glu Likely pathogenic ★ same residue
ACTA1 p.Lys375Asn Likely pathogenic ★ 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

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-lys375 (accessed [today's date]).

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