Is ACTN3 p.Glu635Ala (c.1904A>C) pathogenic?

ACTN3 p.Glu635Ala (c.1904A>C) is classified Benign in ACTN3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-11-12). AlphaMissense: likely benign (0.2297); Common (popmax 18.1%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with ACTN3-related disorder.

What condition is associated with ACTN3 p.Glu635Ala (c.1904A>C)?

ACTN3 p.Glu635Ala (c.1904A>C) is associated with ACTN3-related disorder (ClinVar).

What do computational predictors say about ACTN3 p.Glu635Ala (c.1904A>C)?

AlphaMissense predicts likely benign (score 0.2297) — an in-silico prediction, not a clinical call.

ACTN3 p.Glu635Ala

Q: How common is ACTN3 p.Glu635Ala (c.1904A>C) in the general population?

ACTN3 p.Glu635Ala (c.1904A>C) is common (popmax 18.1%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1904A>C · rs2229456 · VCV3056781

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2297 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 18.1%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

1/2 damaging

AlphaMissense, SaProt

Conditions

ACTN3-related disorder

Computational evidence

Protein change
AlphaMissense	0.2297	likely benign
SaProt	LLR -12.73	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 11	GERP 2.5, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 7,830 bp · p 0.26 · regional, not allelic
Overall
CADD	25.4	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 18.1% European (non-Finnish) · 213,033/1,174,534 alleles

Filtering AF 18.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 18%

Overall 17.5% 280,864/1,600,474 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	21.1%	5
Amishnot grpmax-eligible	20.4%	5
European (non-Finnish)grpmax	18.1%	6
South Asian	17.6%	6
Remaining individualsnot grpmax-eligible	16.6%	6
East Asian	16.2%	6
African / African-American	15.3%	7
Ashkenazi Jewishnot grpmax-eligible	14.2%	7
Middle Eastern	13%	8
Admixed American	8.73%	11

Finnish 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: ACTN3
Protein: p.Glu635Ala
Coding: c.1904A>C
MANE Select: NM_001104
dbSNP: rs2229456
Type: single nucleotide variant
Location: chr11:66561270 (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

Disease context

ACTN3-related disorder

Similar variants

ACTN3 p.Glu635Lys Uncertain significance ★ ⚠ same residue
ACTN3 c.1129-8C>T Likely benign same condition
ACTN3 c.1678-8G>A Benign same condition
ACTN3 p.Ala417Ser Benign same condition
ACTN3 p.Ala469= Likely benign same condition
ACTN3 p.Ala492= Likely benign same condition
ACTN3 p.Ala564= Likely benign same condition
ACTN3 p.Ala881Ser Likely benign ⚠ 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/actn3-p-glu635ala (accessed [today's date]).

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