Is ACTN3 p.Ile699Thr (c.2096T>C) pathogenic?

ACTN3 p.Ile699Thr (c.2096T>C) is classified Uncertain significance in ACTN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: likely benign (0.2739); Ultra-rare (popmax 0.0451%, amr).

How common is ACTN3 p.Ile699Thr (c.2096T>C) in the general population?

ACTN3 p.Ile699Thr (c.2096T>C) is ultra-rare (popmax 0.0451%, amr) (gnomAD).

What do computational predictors say about ACTN3 p.Ile699Thr (c.2096T>C)?

AlphaMissense predicts likely benign (score 0.2739) — an in-silico prediction, not a clinical call.

ACTN3 p.Ile699Thr

c.2096T>C · VCV4222188

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2739 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0451%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt

Computational evidence

Protein change
AlphaMissense	0.2739	likely benign
SaProt	LLR -12.87	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 4.1	GERP 2.5, phastCons 0.93
Regional constraint	o/e 1.04	unconstrained · MANE · 7,830 bp · p 0.26 · regional, not allelic
Overall
CADD	24.4	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 0.0451% Admixed American · 27/59,840 alleles

Filtering AF 0.0318% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0274%

Overall 0.0273% 440/1,612,756 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0451%	2,216
Remaining individualsnot grpmax-eligible	0.0336%	2,973
European (non-Finnish)	0.031%	3,222
African / African-American	0.02%	5,001
South Asian	0.00991%	10,087
East Asian	0.00446%	22,422

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.Ile699Thr
Coding: c.2096T>C
MANE Select: NM_001104
Type: single nucleotide variant
Location: chr11:66561558 (GRCh38)
Gene constraint: LOEUF 0.944 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.61 · 3 PDB
Residue 699: 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.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
ACTN3 p.Ala470Pro 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-ile699thr (accessed [today's date]).

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