Is ACTN3 p.Ala417Ser (c.1249G>T) pathogenic?

ACTN3 p.Ala417Ser (c.1249G>T) is classified Benign in ACTN3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-05-24). AlphaMissense: likely benign (0.1348); Low-frequency (popmax 1.62%, eas); Associated with ACTN3-related disorder.

What condition is associated with ACTN3 p.Ala417Ser (c.1249G>T)?

ACTN3 p.Ala417Ser (c.1249G>T) is associated with ACTN3-related disorder (ClinVar).

How common is ACTN3 p.Ala417Ser (c.1249G>T) in the general population?

ACTN3 p.Ala417Ser (c.1249G>T) is low-frequency (popmax 1.62%, eas) (gnomAD).

What do computational predictors say about ACTN3 p.Ala417Ser (c.1249G>T)?

AlphaMissense predicts likely benign (score 0.1348) — an in-silico prediction, not a clinical call.

ACTN3 p.Ala417Ser

c.1249G>T · rs201812719 · VCV3039054

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1348 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.62%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Conditions

ACTN3-related disorder

Computational evidence

Protein change
AlphaMissense	0.1348	likely benign
SaProt	LLR -6.51	tolerated
⇒ AlphaMissense and SaProt both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.5, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 7,830 bp · p 0.26 · regional, not allelic
Overall
CADD	22.4	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 1.62% East Asian · 726/44,880 alleles

Filtering AF 1.52% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.48%

Overall 0.0553% 893/1,613,712 alleles · low-frequency

Ancestry group	Frequency	1 in
East Asiangrpmax	1.62%	62
Remaining individualsnot grpmax-eligible	0.0976%	1,024
Ashkenazi Jewishnot grpmax-eligible	0.0642%	1,558
African / African-American	0.06%	1,668
Middle Eastern	0.033%	3,031
South Asian	0.0263%	3,795
Admixed American	0.00666%	15,006
European (non-Finnish)	0.00102%	98,326

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.Ala417Ser
Coding: c.1249G>T
MANE Select: NM_001104
dbSNP: rs201812719
Type: single nucleotide variant
Location: chr11:66558147 (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 c.1129-8C>T Likely benign same condition
ACTN3 c.1678-8G>A 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.Arg199Gln 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-ala417ser (accessed [today's date]).

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