ACTN2

Chr 1AD

actinin alpha 2

Also known as: CMD1AA, CMH23, CMYO8, CMYP8, MPD6, MYOCOZ

NCBI Gene: 88 ENSG00000077522 UniProt: P35609

Alpha actinins belong to the spectrin gene superfamily which represents a diverse group of cytoskeletal proteins, including the alpha and beta spectrins and dystrophins. Alpha actinin is an actin-binding protein with multiple roles in different cell types. In nonmuscle cells, the cytoskeletal isoform is found along microfilament bundles and adherens-type junctions, where it is involved in binding actin to the membrane. In contrast, skeletal, cardiac, and smooth muscle isoforms are localized to the Z-disc and analogous dense bodies, where they help anchor the myofibrillar actin filaments. This gene encodes a muscle-specific, alpha actinin isoform that is expressed in both skeletal and cardiac muscles. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2013]

Primary Disease Associations & Inheritance

Cardiomyopathy, dilated, 1AA, with or without LVNCMIM #612158

Cardiomyopathy, hypertrophic, 23, with or without LVNCMIM #612158

Congenital myopathy 8MIM #618654

Myopathy, distal, 6, adult onsetMIM #618655

UniProtCardiomyopathy, familial hypertrophic, 23, with or without left ventricular non-compaction

Active trials

Pathogenic / LP

395

ClinVar variants

Pubs (1 yr)

1.3

Missense Z

0.24

LOEUF· LoF intolerant

Clinical Summary— ACTN2

🧬

Gene-Disease Validity (ClinGen)

ACTN2-related cardiac and skeletal myopathy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

📋

ClinVar Variants

15 Pathogenic / Likely Pathogenic· 225 VUS of 395 total submissions

📖

GeneReview available — ACTN2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.24LOEUF

pLI 1.000

Z-score 5.73

OE 0.12 (0.07–0.24)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

1.29Z-score

OE missense 0.84 (0.78–0.91)

446 obs / 529.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.12 (0.07–0.24)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.84 (0.78–0.91)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.97

0≤1.21.6

LoF obs/exp: 6 / 49.6Missense obs/exp: 446 / 529.7Syn Z: 0.33

0.6164th %ile

GOF

0.78top 25%

LOF

0.4233th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF20% of P/LP variants are LoF · LOEUF 0.24

GOFprediction above median

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.