Is ACTN2 p.Arg759Thr (c.2276G>C) pathogenic?

ACTN2 p.Arg759Thr (c.2276G>C) is classified Pathogenic in ACTN2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2006-12-29). AlphaMissense: likely pathogenic (0.9418); Absent from gnomAD v4.1; Associated with cardiomyopathy, familial hypertrophic, 23, with or without ventricular noncompaction.

How common is ACTN2 p.Arg759Thr (c.2276G>C) in the general population?

ACTN2 p.Arg759Thr (c.2276G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTN2 p.Arg759Thr (c.2276G>C)?

AlphaMissense predicts likely pathogenic (score 0.9418) — an in-silico prediction, not a clinical call.

ACTN2 p.Arg759Thr

Q: What condition is associated with ACTN2 p.Arg759Thr (c.2276G>C)?

ACTN2 p.Arg759Thr (c.2276G>C) is associated with cardiomyopathy, familial hypertrophic, 23, with or without ventricular noncompaction (ClinVar).

c.2276G>C · rs786204950 · VCV189516

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9418 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cardiomyopathy, familial hypertrophic, 23, with or without ventricular noncompaction

Computational evidence

Protein change
AlphaMissense	0.9418	likely pathogenic ✓ concordant with ClinVar
REVEL	0.685	pathogenic-leaning
SaProt	LLR -10.99	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 25 kb · p 0.0054 · regional, not allelic
Overall
CADD	27.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACTN2
Protein: p.Arg759Thr
Coding: c.2276G>C
MANE Select: NM_001103
dbSNP: rs786204950
Type: single nucleotide variant
Location: chr1:236757607 (GRCh38)
Gene constraint: LOEUF 0.432 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.88 · 18 PDB
Residue 759: the ef-hand 1 domain; an α-helix

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

Disease context

cardiomyopathy, familial hypertrophic, 23, with or without ventricular noncompaction — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACTN2 p.Arg759Gly Uncertain significance ★ ⚠ same residue
ACTN2 p.Arg759Ser Uncertain significance ★ ⚠ same residue
ACTN2 p.Arg759= Likely benign ★ same residue
ACTN2 p.Ala119Thr Pathogenic/Likely pathogenic ★★ same condition
ACTN2 p.Gly111Val Uncertain significance ★ ⚠ same condition
ACTN2 p.Thr495Met Conflicting classifications of pathogenicity ★ ⚠ same condition
ACTN2 p.Glu628Gly Pathogenic same condition
ACTN2 p.Leu727Arg Pathogenic/Likely pathogenic ★★ same type

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-arg759thr (accessed [today's date]).

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