Is ACTN3 p.Glu867Lys (c.2599G>A) pathogenic?

ACTN3 p.Glu867Lys (c.2599G>A) is classified Uncertain significance in ACTN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-03). AlphaMissense: likely benign (0.2282); Rare (popmax 0.134%, eas).

How common is ACTN3 p.Glu867Lys (c.2599G>A) in the general population?

ACTN3 p.Glu867Lys (c.2599G>A) is rare (popmax 0.134%, eas) (gnomAD).

What do computational predictors say about ACTN3 p.Glu867Lys (c.2599G>A)?

AlphaMissense predicts likely benign (score 0.2282) — an in-silico prediction, not a clinical call.

ACTN3 p.Glu867Lys

c.2599G>A · VCV4222146

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2282 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.134%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt

Computational evidence

Protein change
AlphaMissense	0.2282	likely benign
SaProt	LLR -12.80	damaging
⇒ SaProt calls this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.3	GERP 2.5, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 7,830 bp · p 0.26 · regional, not allelic
Overall
CADD	25.7	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 0.134% East Asian · 60/44,848 alleles

Filtering AF 0.107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0968%

Overall 0.00583% 94/1,613,180 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.134%	747
African / African-American	0.0213%	4,689
South Asian	0.00439%	22,764
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,592
Admixed American	0.00167%	59,992
European (non-Finnish)	0.00102%	98,310

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: ACTN3
Protein: p.Glu867Lys
Coding: c.2599G>A
MANE Select: NM_001104
Type: single nucleotide variant
Location: chr11:66563086 (GRCh38)
Gene constraint: LOEUF 0.944 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.61 · 3 PDB
Residue 867: a UniProt-annotated variant site (very low expression, if any, at the protein level in skeletal muscle)

Full ACTN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACTN3 p.Ala115Asp Uncertain significance ★ ⚠ same type
ACTN3 p.Ala149Thr Uncertain significance ★ ⚠ same type
ACTN3 p.Ala251Thr Uncertain significance ★ ⚠ same type
ACTN3 p.Ala410Pro Uncertain significance ★ ⚠ same type
ACTN3 p.Ala410Val Uncertain significance ★ ⚠ same type
ACTN3 p.Ala460Val Uncertain significance ★ ⚠ same type
ACTN3 p.Ala469Gly Uncertain significance ★ ⚠ same type
ACTN3 p.Ala470Pro 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/actn3-p-glu867lys (accessed [today's date]).

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