Is ACTN2 p.Ala274Pro (c.820G>C) pathogenic?

ACTN2 p.Ala274Pro (c.820G>C) is classified Uncertain significance in ACTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-01). AlphaMissense: likely pathogenic (0.9858); Absent from gnomAD v4.1.

How common is ACTN2 p.Ala274Pro (c.820G>C) in the general population?

ACTN2 p.Ala274Pro (c.820G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTN2 p.Ala274Pro (c.820G>C)?

AlphaMissense predicts likely pathogenic (score 0.9858) — an in-silico prediction, not a clinical call.

ACTN2 p.Ala274Pro

c.820G>C · rs2527591952 · VCV2640111

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9858 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9858	likely pathogenic
REVEL	0.31	indeterminate
SaProt	LLR -11.10	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 50 kb · p 1.6e-10 · regional, not allelic
Overall
CADD	29.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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.Ala274Pro
Coding: c.820G>C
MANE Select: NM_001103
dbSNP: rs2527591952
Type: single nucleotide variant
Location: chr1:236737158 (GRCh38)
Gene constraint: LOEUF 0.432 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.88 · 18 PDB
Residue 274: an α-helix

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

Similar variants

ACTN2 p.Ala119Thr Pathogenic/Likely pathogenic ★★ same type
ACTN2 p.Leu727Arg Pathogenic/Likely pathogenic ★★ same type
ACTN2 p.Thr247Met Likely pathogenic ★★ same type
ACTN2 c.1107+3G>A Uncertain significance ★★ same type
ACTN2 c.1108-10A>G Uncertain significance ★★ same type
ACTN2 c.1255+1G>C Uncertain significance ★★ same type
ACTN2 c.126+2T>G Uncertain significance ★★ same type
ACTN2 c.127-3C>A Uncertain significance ★★ 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-ala274pro (accessed [today's date]).

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