Is ACTN2 p.Glu305Ala (c.914A>C) pathogenic?

ACTN2 p.Glu305Ala (c.914A>C) is classified Likely benign in ACTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-08). AlphaMissense: likely benign (0.317); Very rare (popmax 0.00223%, eas); Associated with familial hypertrophic cardiomyopathy.

What condition is associated with ACTN2 p.Glu305Ala (c.914A>C)?

ACTN2 p.Glu305Ala (c.914A>C) is associated with familial hypertrophic cardiomyopathy, dilated cardiomyopathy 1AA (ClinVar).

How common is ACTN2 p.Glu305Ala (c.914A>C) in the general population?

ACTN2 p.Glu305Ala (c.914A>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ACTN2 p.Glu305Ala (c.914A>C)?

AlphaMissense predicts likely benign (score 0.317) — an in-silico prediction, not a clinical call.

ACTN2 p.Glu305Ala

c.914A>C · rs751349296 · VCV1928186

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.317 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

familial hypertrophic cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.317	likely benign
REVEL	0.383	indeterminate
SaProt	LLR -13.64	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 25 kb · p 0.0054 · regional, not allelic
Overall
CADD	25.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,864 alleles

Overall 6.2e-05% 1/1,614,040 alleles · very rare exomes 1/1,461,892 · genomes 0/152,148 · joint denominator

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: ACTN2
Protein: p.Glu305Ala
Coding: c.914A>C
MANE Select: NM_001103
dbSNP: rs751349296
Type: single nucleotide variant
Location: chr1:236739339 (GRCh38)
Gene constraint: LOEUF 0.432 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.88 · 18 PDB

Full ACTN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial hypertrophic cardiomyopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dilated cardiomyopathy 1AA

Similar variants

ACTN2 p.Glu305= Likely benign ★ same residue
ACTN2 p.Ala119Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
ACTN2 p.Thr247Met Likely pathogenic ★★ same condition
ACTN2 c.1107+3G>A Uncertain significance ★★ same condition
ACTN2 c.1108-10A>G Uncertain significance ★★ same condition
ACTN2 c.1255+1G>C Uncertain significance ★★ same condition
ACTN2 c.126+2T>G Uncertain significance ★★ same condition
ACTN2 c.127-3C>A Uncertain significance ★★ 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/actn2-p-glu305ala (accessed [today's date]).

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