Is ACTN3 p.Arg646Gln (c.1937G>A) pathogenic?

ACTN3 p.Arg646Gln (c.1937G>A) is classified Uncertain significance in ACTN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-24). AlphaMissense: likely benign (0.2073); Ultra-rare (popmax 0.0186%, mid).

How common is ACTN3 p.Arg646Gln (c.1937G>A) in the general population?

ACTN3 p.Arg646Gln (c.1937G>A) is ultra-rare (popmax 0.0186%, mid) (gnomAD).

What do computational predictors say about ACTN3 p.Arg646Gln (c.1937G>A)?

AlphaMissense predicts likely benign (score 0.2073) — an in-silico prediction, not a clinical call.

ACTN3 p.Arg646Gln

c.1937G>A · rs565643850 · VCV2402010

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2073 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0186%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt

Computational evidence

Protein change
AlphaMissense	0.2073	likely benign
SaProt	LLR -13.31	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 9.9	GERP 2.5, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 7,830 bp · p 0.26 · regional, not allelic
Overall
CADD	28.5	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 0.0186% Middle Eastern · 1/5,378 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00067%

Overall 0.00149% 24/1,610,158 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0186%	5,378
Admixed American	0.00502%	19,905
Finnishnot grpmax-eligible	0.00315%	31,719
South Asian	0.00221%	45,166
European (non-Finnish)	0.00136%	73,683

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.Arg646Gln
Coding: c.1937G>A
MANE Select: NM_001104
dbSNP: rs565643850
Type: single nucleotide variant
Location: chr11:66561303 (GRCh38)
Gene constraint: LOEUF 0.944 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.61 · 3 PDB
Residue 646: 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.Arg646Trp 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
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-arg646gln (accessed [today's date]).

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