Is ACTN2 p.Arg852Gln (c.2555G>A) pathogenic?

ACTN2 p.Arg852Gln (c.2555G>A) is classified Conflicting classifications of pathogenicity in ACTN2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.1412); Ultra-rare (popmax 0.0164%, mid); Associated with intrinsic cardiomyopathy.

What condition is associated with ACTN2 p.Arg852Gln (c.2555G>A)?

ACTN2 p.Arg852Gln (c.2555G>A) is associated with intrinsic cardiomyopathy, dilated cardiomyopathy 1AA, familial hypertrophic cardiomyopathy (ClinVar).

How common is ACTN2 p.Arg852Gln (c.2555G>A) in the general population?

ACTN2 p.Arg852Gln (c.2555G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about ACTN2 p.Arg852Gln (c.2555G>A)?

AlphaMissense predicts likely benign (score 0.1412) — an in-silico prediction, not a clinical call.

ACTN2 p.Arg852Gln

c.2555G>A · rs727502888 · VCV162745

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1412 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

intrinsic cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.1412	likely benign
REVEL	0.367	indeterminate
SaProt	LLR -10.10	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 25 kb · p 0.0054 · regional, not allelic
Overall
CADD	28.6	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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00421% 68/1,613,986 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.125%	800
Middle Easterngrpmax	0.0164%	6,082
Remaining individualsnot grpmax-eligible	0.0112%	8,925
East Asian	0.00223%	44,902
South Asian	0.0022%	45,535
European (non-Finnish)	0.00169%	59,000

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg852Gln
Coding: c.2555G>A
MANE Select: NM_001103
dbSNP: rs727502888
Type: single nucleotide variant
Location: chr1:236762489 (GRCh38)
Gene constraint: LOEUF 0.432 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.88 · 18 PDB
Residue 852: an α-helix

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

Disease context

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

Also linked: dilated cardiomyopathy 1AA familial hypertrophic cardiomyopathy

Similar variants

ACTN2 p.Arg852Trp Uncertain significance ★★ ⚠ 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-arg852gln (accessed [today's date]).

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