ACTN2 (Alpha-actinin-2) variants and mutations

ACTN2 (also known as Alpha-actinin-2) is a human protein-coding gene encoding an alpha-actinin-2 protein. It crosslinks actin at the sarcomeric Z-disc and organizes mechanical and signaling complexes in cardiac and skeletal muscle. Pathogenic variants can cause hypertrophic, dilated, or other inherited cardiomyopathies and occasional skeletal-muscle phenotypes. This analysis covers 1,713 ACTN2 variants and mutations. Of these, 71% have computational variant effect predictions. Disease context includes dilated cardiomyopathy 1AA, myopathy, congenital, with structured cores and z-line abnormalities, and Rare familial disorder with hypertrophic cardiomyopathy. Example ACTN2 variants include M1V, N2I, and N2K.

Variant analysis overview

Gene: ACTN2
Protein: Alpha-actinin-2
UniProt accession: P35609
Organism: Homo sapiens
Variants analyzed: 1713
Variant scope: all variants
Completed: 2026-08-18

Variant and mutation evidence

Variant composition: 1,501 unspecified-consequence records; 114 missense variants; 72 synonymous variants; 10 stop-gained variants; 11 frameshift variants; 2 in-frame deletions; 1 splice-region variants; 2 substitution
Prediction scores: 1,219 variants have prediction scores (71% of the analyzed set).

Clinical, disease, and population context

Disease context: 25 disease associations are represented. Top associations: dilated cardiomyopathy 1AA, myopathy, congenital, with structured cores and z-line abnormalities, Rare familial disorder with hypertrophic cardiomyopathy, autosomal dominant dilated cardiomyopathy, neurodegenerative disease, cardiomyopathy, familial hypertrophic, 23, with or without ventricular noncompac, intrinsic cardiomyopathy, myopathy, distal, 6, adult-onset, autosomal dominant, familial hypertrophic cardiomyopathy, ACTN2-related cardiac and skeletal myopathy, heart failure, hypertrophic cardiomyopathy.

Protein structure and variant hotspots

Protein features: 4 domains; 6 binding sites; 1 post-translational modification sites.
Structural context: 514 variants have structural context.
PTM context: 2 variants overlap post-translational modification sites.

Data sources

Evidence in this analysis draws on EBI Proteins Variation, UniProt, gnomAD v4, EuropePMC, 3D Hotspot Analysis, Interaction Network Analysis, Protein Data Bank, AlphaFold DB, gnomAD constraint, Open Targets, MaveDB, LitVar.

Notable ACTN2 variants

Examples include M1V, N2I, N2K, N2Y, N2S, N2N, Q3H, Q3R. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.

ACTN2 analysis run — ACTN2 (1,713 variants) — completed 2026-08-18