Is ACTN3 p.Arg314Cys (c.940C>T) pathogenic?

ACTN3 p.Arg314Cys (c.940C>T) is classified Benign in ACTN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-01). AlphaMissense: ambiguous (0.4146); Rare (popmax 0.989%, sas).

How common is ACTN3 p.Arg314Cys (c.940C>T) in the general population?

ACTN3 p.Arg314Cys (c.940C>T) is rare (popmax 0.989%, sas) (gnomAD).

What do computational predictors say about ACTN3 p.Arg314Cys (c.940C>T)?

AlphaMissense predicts ambiguous (score 0.4146) — an in-silico prediction, not a clinical call.

ACTN3 p.Arg314Cys

c.940C>T · rs200574979 · VCV2641993

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4146 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.989%, sas)

Computational evidence

Protein change
AlphaMissense	0.4146	ambiguous
SaProt	LLR -14.15	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.3, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 7,830 bp · p 0.26 · regional, not allelic
Overall
CADD	26.6	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 0.989% South Asian · 899/90,914 alleles

Filtering AF 0.935% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.914%

Overall 0.0674% 1,087/1,613,392 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.989%	101
Middle Eastern	0.33%	303
Remaining individualsnot grpmax-eligible	0.064%	1,562
African / African-American	0.0187%	5,360
European (non-Finnish)	0.00932%	10,725
Admixed American	0.00501%	19,977
East Asian	0.00223%	44,854

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.Arg314Cys
Coding: c.940C>T
MANE Select: NM_001104
dbSNP: rs200574979
Type: single nucleotide variant
Location: chr11:66557741 (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

Similar variants

ACTN3 p.Arg314His Uncertain significance ★ ⚠ same residue
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

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-arg314cys (accessed [today's date]).

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