Is ACTN3 p.Glu635Lys (c.1903G>A) pathogenic?

ACTN3 p.Glu635Lys (c.1903G>A) is classified Uncertain significance in ACTN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-02). AlphaMissense: ambiguous (0.4423); Very rare (popmax 0.00669%, afr).

How common is ACTN3 p.Glu635Lys (c.1903G>A) in the general population?

ACTN3 p.Glu635Lys (c.1903G>A) is very rare (popmax 0.00669%, afr) (gnomAD).

What do computational predictors say about ACTN3 p.Glu635Lys (c.1903G>A)?

AlphaMissense predicts ambiguous (score 0.4423) — an in-silico prediction, not a clinical call.

ACTN3 p.Glu635Lys

c.1903G>A · rs755463676 · VCV2305008

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4423 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, afr)

Computational evidence

Protein change
AlphaMissense	0.4423	ambiguous
SaProt	LLR -13.51	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 7,830 bp · p 0.26 · regional, not allelic
Overall
CADD	27.3	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 0.00669% African / African-American · 5/74,694 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.000687% 11/1,601,854 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00669%	14,939
East Asian	0.00225%	44,440
South Asian	0.00112%	88,942
European (non-Finnish)	0.00034%	293,860

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.Glu635Lys
Coding: c.1903G>A
MANE Select: NM_001104
dbSNP: rs755463676
Type: single nucleotide variant
Location: chr11:66561269 (GRCh38)
Gene constraint: LOEUF 0.944 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.61 · 3 PDB
Residue 635: a UniProt-annotated variant site (very low expression, if any, at the protein level in skeletal muscle); a UniProt-annotated variant site (in)

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

Similar variants

ACTN3 p.Glu635Ala Benign ⚠ same residue
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

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-glu635lys (accessed [today's date]).

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