Sugi Variant
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ACTN3/p.Arg686Gln

ACTN3 p.Arg686Gln

c.2057G>A · rs375257311 · VCV2475745

Uncertain significance Single submitter
Classification
Uncertain significance
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
AlphaMissense
likely benign
0.0807 · ACMG-weighted
gnomAD v4.1
Rare
ultra-rare (popmax 0.0102%, amr)
Missense predictors
0/2 damaging
AlphaMissense, SaProt

Computational evidence

Protein change
AlphaMissense0.0807likely benign
SaProtLLR -7.24tolerated
⇒ AlphaMissense and SaProt both call this tolerated.
Splicing
SpliceAI—not assessed · no allele here is in the release
Constraint at this position
ConservationphyloP 3GERP 2.5, phastCons 1
Regional constrainto/e 1.04unconstrained · MANE · 7,830 bp · p 0.26 · regional, not allelic
Overall
CADD24.6PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes
Grpmax group 0.0102% Admixed American · 6/58,900 alleles
Filtering AF 0.00793% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00746%
Overall 0.00796% 128/1,607,340 alleles · ultra-rare
Ancestry group Frequency 1 in
Remaining individualsnot grpmax-eligible 0.0129% 7,774
Admixed Americangrpmax 0.0102% 9,817
European (non-Finnish) 0.00943% 10,604
Ashkenazi Jewishnot grpmax-eligible 0.0034% 29,424
East Asian 0.00224% 44,638
African / African-American 0.00134% 74,858

Remaining individuals 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.Arg686Gln
Coding
c.2057G>A
MANE Select
NM_001104
dbSNP
rs375257311
Type
single nucleotide variant
Location
chr11:66561519 (GRCh38)
Gene constraint
LOEUF 0.944 · pLI <0.01 (gnomAD)
Structure
AlphaFold pLDDT 84.61 · 3 PDB
Residue 686
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

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-arg686gln (accessed [today's date]).

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