Is ACTN3 p.Ala469= (c.1407C>T) pathogenic?

ACTN3 p.Ala469= (c.1407C>T) is classified Likely benign in ACTN3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-07-18). Ultra-rare (popmax 0.0126%, nfe); Associated with ACTN3-related disorder.

What condition is associated with ACTN3 p.Ala469= (c.1407C>T)?

ACTN3 p.Ala469= (c.1407C>T) is associated with ACTN3-related disorder (ClinVar).

How common is ACTN3 p.Ala469= (c.1407C>T) in the general population?

ACTN3 p.Ala469= (c.1407C>T) is ultra-rare (popmax 0.0126%, nfe) (gnomAD).

ACTN3 p.Ala469=

c.1407C>T · rs376311597 · VCV3049744

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0126%, nfe)

Conditions

ACTN3-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -5.1
Overall
CADD	0.134	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0126% European (non-Finnish) · 146/1,155,428 alleles

Filtering AF 0.0109% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0103%

Overall 0.00998% 155/1,553,094 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0126%	7,914
Finnishnot grpmax-eligible	0.00644%	15,538
Remaining individualsnot grpmax-eligible	0.00335%	29,816
African / African-American	0.00285%	35,041
East Asian	0.00249%	40,134

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.Ala469=
Coding: c.1407C>T
MANE Select: NM_001104
dbSNP: rs376311597
Type: single nucleotide variant
Location: chr11:66559366 (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

Disease context

ACTN3-related disorder

Similar variants

ACTN3 p.Ala469Gly Uncertain significance ★ ⚠ same residue
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.Ala492= Likely benign same condition
ACTN3 p.Ala564= Likely benign same condition
ACTN3 p.Ala881Ser Likely benign ⚠ same condition
ACTN3 p.Arg199Gln Likely 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-ala469 (accessed [today's date]).

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