Is ACTN2 p.Arg796His (c.2387G>A) pathogenic?

ACTN2 p.Arg796His (c.2387G>A) is classified Uncertain significance in ACTN2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-09). AlphaMissense: ambiguous (0.4752); Very rare (popmax 0.00446%, eas); Associated with Cardiovascular phenotype.

What condition is associated with ACTN2 p.Arg796His (c.2387G>A)?

ACTN2 p.Arg796His (c.2387G>A) is associated with Cardiovascular phenotype, dilated cardiomyopathy 1AA, familial hypertrophic cardiomyopathy (ClinVar).

How common is ACTN2 p.Arg796His (c.2387G>A) in the general population?

ACTN2 p.Arg796His (c.2387G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about ACTN2 p.Arg796His (c.2387G>A)?

AlphaMissense predicts ambiguous (score 0.4752) — an in-silico prediction, not a clinical call.

ACTN2 p.Arg796His

c.2387G>A · rs772409484 · VCV852397

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4752 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.4752	ambiguous
REVEL	0.649	pathogenic-leaning
SaProt	LLR -7.17	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.26 · evaluated, not missing
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	32.0	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 0.00446% East Asian · 2/44,888 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000867% 14/1,614,020 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,444
South Asian	0.00329%	30,360
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	0.000678%	147,506

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.Arg796His
Coding: c.2387G>A
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

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dilated cardiomyopathy 1AA familial hypertrophic cardiomyopathy

Similar variants

ACTN2 p.Arg796Cys Uncertain significance ★★ ⚠ same residue
ACTN2 p.Arg796Leu Uncertain significance ★★ ⚠ same residue
ACTN2 p.Arg796= 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

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-arg796his (accessed [today's date]).

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