Is ACTN2 p.Glu63Lys (c.187G>A) pathogenic?

ACTN2 p.Glu63Lys (c.187G>A) is classified Uncertain significance in ACTN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-02). AlphaMissense: likely pathogenic (0.9247); Very rare (popmax 0.00133%, afr); Associated with Cardiovascular phenotype.

What condition is associated with ACTN2 p.Glu63Lys (c.187G>A)?

ACTN2 p.Glu63Lys (c.187G>A) is associated with Cardiovascular phenotype (ClinVar).

How common is ACTN2 p.Glu63Lys (c.187G>A) in the general population?

ACTN2 p.Glu63Lys (c.187G>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ACTN2 p.Glu63Lys (c.187G>A)?

AlphaMissense predicts likely pathogenic (score 0.9247) — an in-silico prediction, not a clinical call.

ACTN2 p.Glu63Lys

c.187G>A · VCV3911854

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9247 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9247	likely pathogenic
REVEL	0.341	indeterminate
SaProt	LLR -14.97	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
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 0.65	unconstrained · MANE · 50 kb · p 1.6e-10 · regional, not allelic
Overall
CADD	28.5	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

Grpmax group 0.00133% African / African-American · 1/75,022 alleles

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

Overall 0.000205% 3/1,461,852 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,022
European (non-Finnish)	0.000169%	589,995

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.Glu63Lys
Coding: c.187G>A
MANE Select: NM_001103
Type: single nucleotide variant
Location: chr1:236717918 (GRCh38)
Gene constraint: LOEUF 0.432 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.88 · 18 PDB
Residue 63: the calponin-homology (ch) 1 domain; a turn; the 'actin-binding' region

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

Similar variants

ACTN2 p.Glu63= Likely benign ★ same residue
ACTN2 c.1255+1G>C Uncertain significance ★★ same condition
ACTN2 c.126+2T>G Uncertain significance ★★ same condition
ACTN2 c.2154+4C>T Uncertain significance ★★ same condition
ACTN2 c.697+1G>A Uncertain significance ★★ same condition
ACTN2 c.783+4C>T Uncertain significance ★★ same condition
ACTN2 c.*10T>C Uncertain significance ★★ same condition
ACTN2 p.Ala142Val 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-glu63lys (accessed [today's date]).

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