Is ACTN3 p.Arg334Gln (c.1001G>A) pathogenic?

ACTN3 p.Arg334Gln (c.1001G>A) is classified Uncertain significance in ACTN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-04). AlphaMissense: ambiguous (0.3871); Ultra-rare (popmax 0.02%, amr).

How common is ACTN3 p.Arg334Gln (c.1001G>A) in the general population?

ACTN3 p.Arg334Gln (c.1001G>A) is ultra-rare (popmax 0.02%, amr) (gnomAD).

What do computational predictors say about ACTN3 p.Arg334Gln (c.1001G>A)?

AlphaMissense predicts ambiguous (score 0.3871) — an in-silico prediction, not a clinical call.

ACTN3 p.Arg334Gln

c.1001G>A · VCV4637135

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3871 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, amr)

Computational evidence

Protein change
AlphaMissense	0.3871	ambiguous
SaProt	LLR -13.35	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 7,830 bp · p 0.26 · regional, not allelic
Overall
CADD	33.0	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 0.02% Admixed American · 12/59,964 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.0018% 29/1,613,818 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.02%	4,997
East Asian	0.00668%	14,961
Remaining individualsnot grpmax-eligible	0.0032%	31,236
African / African-American	0.00133%	74,916
South Asian	0.0011%	91,038
European (non-Finnish)	0.000848%	117,993

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.Arg334Gln
Coding: c.1001G>A
MANE Select: NM_001104
Type: single nucleotide variant
Location: chr11:66557802 (GRCh38)
Gene constraint: LOEUF 0.944 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.61 · 3 PDB

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

Similar variants

ACTN3 p.Arg334Gly Uncertain significance ★ ⚠ same residue
ACTN3 p.Arg334Trp Uncertain significance ★ ⚠ 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

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-arg334gln (accessed [today's date]).

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