Is ACTN3 p.Ala650Val (c.1949C>T) pathogenic?

ACTN3 p.Ala650Val (c.1949C>T) is classified Uncertain significance in ACTN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-14). AlphaMissense: likely pathogenic (0.8279); Very rare (popmax 0.00553%, sas).

How common is ACTN3 p.Ala650Val (c.1949C>T) in the general population?

ACTN3 p.Ala650Val (c.1949C>T) is very rare (popmax 0.00553%, sas) (gnomAD).

What do computational predictors say about ACTN3 p.Ala650Val (c.1949C>T)?

AlphaMissense predicts likely pathogenic (score 0.8279) — an in-silico prediction, not a clinical call.

ACTN3 p.Ala650Val

c.1949C>T · rs760434035 · VCV2389538

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8279 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00553%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt

Computational evidence

Protein change
AlphaMissense	0.8279	likely pathogenic
SaProt	LLR -12.76	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 6	GERP -1.2, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 7,830 bp · p 0.26 · regional, not allelic
Overall
CADD	26.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00553% South Asian · 5/90,400 alleles

Filtering AF 0.00318% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00287%

Overall 0.00366% 59/1,610,472 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00642%	15,577
South Asiangrpmax	0.00553%	18,080
European (non-Finnish)	0.00416%	24,057
Admixed American	0.00167%	59,710

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.Ala650Val
Coding: c.1949C>T
MANE Select: NM_001104
dbSNP: rs760434035
Type: single nucleotide variant
Location: chr11:66561315 (GRCh38)
Gene constraint: LOEUF 0.944 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.61 · 3 PDB
Residue 650: 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-ala650val (accessed [today's date]).

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