Is ACTN3 p.Arg199Gln (c.596G>A) pathogenic?

ACTN3 p.Arg199Gln (c.596G>A) is classified Likely benign in ACTN3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-06-17). AlphaMissense: likely pathogenic (0.6815); Ultra-rare (popmax 0.0369%, nfe); Associated with ACTN3-related disorder.

What condition is associated with ACTN3 p.Arg199Gln (c.596G>A)?

ACTN3 p.Arg199Gln (c.596G>A) is associated with ACTN3-related disorder (ClinVar).

How common is ACTN3 p.Arg199Gln (c.596G>A) in the general population?

ACTN3 p.Arg199Gln (c.596G>A) is ultra-rare (popmax 0.0369%, nfe) (gnomAD).

What do computational predictors say about ACTN3 p.Arg199Gln (c.596G>A)?

AlphaMissense predicts likely pathogenic (score 0.6815) — an in-silico prediction, not a clinical call.

ACTN3 p.Arg199Gln

c.596G>A · rs34515982 · VCV3033075

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6815 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0369%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt

Conditions

ACTN3-related disorder

Computational evidence

Protein change
AlphaMissense	0.6815	likely pathogenic
SaProt	LLR -13.76	damaging
⇒ AlphaMissense and SaProt both call this damaging.
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 0.58	unconstrained · MANE · 770 bp · p 0.00011 · regional, not allelic
Overall
CADD	32.0	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 0.0369% European (non-Finnish) · 435/1,179,958 alleles

Filtering AF 0.034% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0328%

Overall 0.141% 2,270/1,613,880 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	5.28%	19
Remaining individualsnot grpmax-eligible	0.4%	250
European (non-Finnish)grpmax	0.0369%	2,713
Admixed American	0.015%	6,662
South Asian	0.00988%	10,118
African / African-American	0.00667%	14,984

Ashkenazi Jewish 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.Arg199Gln
Coding: c.596G>A
MANE Select: NM_001104
dbSNP: rs34515982
Type: single nucleotide variant
Location: chr11:66555168 (GRCh38)
Gene constraint: LOEUF 0.944 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.61 · 3 PDB
Residue 199: the calponin-homology (ch) 2 domain; an α-helix; the 'actin-binding' region

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

Disease context

ACTN3-related disorder

Similar variants

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
ACTN3 p.Arg211Gln 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-arg199gln (accessed [today's date]).

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