Is ACTN2 p.Arg796Leu (c.2387G>T) pathogenic?

ACTN2 p.Arg796Leu (c.2387G>T) is classified Uncertain significance in ACTN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-01-24). AlphaMissense: likely pathogenic (0.8946); Very rare (popmax 0.000169%, nfe); Associated with myopathy, congenital, with structured cores and z-line abnormalities.

What condition is associated with ACTN2 p.Arg796Leu (c.2387G>T)?

ACTN2 p.Arg796Leu (c.2387G>T) is associated with myopathy, congenital, with structured cores and z-line abnormalities, dilated cardiomyopathy 1AA, familial hypertrophic cardiomyopathy (ClinVar).

How common is ACTN2 p.Arg796Leu (c.2387G>T) in the general population?

ACTN2 p.Arg796Leu (c.2387G>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about ACTN2 p.Arg796Leu (c.2387G>T)?

AlphaMissense predicts likely pathogenic (score 0.8946) — an in-silico prediction, not a clinical call.

ACTN2 p.Arg796Leu

c.2387G>T · rs772409484 · VCV222485

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8946 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

myopathy, congenital, with structured cores and z-line abnormalities

Computational evidence

Protein change
AlphaMissense	0.8946	likely pathogenic
REVEL	0.796	moderately pathogenic-leaning
SaProt	LLR -9.87	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	Δ0.26	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 12	GERP 1.3, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 25 kb · p 0.0054 · regional, not allelic
Overall
CADD	33.0	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 0.000169% European (non-Finnish) · 2/1,180,040 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,886 alleles · very rare

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.Arg796Leu
Coding: c.2387G>T
MANE Select: NM_001103
dbSNP: rs772409484
Type: single nucleotide variant
Location: chr1:236761034 (GRCh38)
Gene constraint: LOEUF 0.432 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.88 · 18 PDB
Residue 796: an α-helix; the ef-hand 2 domain

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

Disease context

myopathy, congenital, with structured cores and z-line abnormalities — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dilated cardiomyopathy 1AA familial hypertrophic cardiomyopathy myopathy, distal, 6, adult-onset, autosomal dominant

Similar variants

ACTN2 p.Arg796Cys Uncertain significance ★★ ⚠ same residue
ACTN2 p.Arg796His Uncertain significance ★★ ⚠ same residue
ACTN2 p.Arg796= Likely benign ★ same residue
ACTN2 p.Ala119Thr Pathogenic/Likely pathogenic ★★ same condition
ACTN2 p.Leu727Arg 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

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-arg796leu (accessed [today's date]).

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