ACTN2
Chr 1ADactinin alpha 2
Also known as: CMD1AA, CMH23, CMYO8, CMYP8, MPD6, MYOCOZ
Alpha-actinin-2 is an F-actin cross-linking protein that anchors actin filaments to the Z-disc in skeletal and cardiac muscle. Mutations cause autosomal dominant cardiomyopathies (dilated and hypertrophic, with or without left ventricular noncompaction), congenital myopathy, and adult-onset distal myopathy. The gene is extremely intolerant to loss-of-function variants (pLI >0.99), indicating that complete loss of function is likely incompatible with normal development.
Definitive — sufficient evidence for diagnostic panels
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly LoF-intolerant (top ~10% of genes)
Mild missense constraint
This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
ClinVar Variant Classifications
0 submitted variants in ClinVar
Protein Context — Lollipop Plot
ACTN2 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools