Is ACTN3 p.Cys628Arg (c.1882T>C) pathogenic?

ACTN3 p.Cys628Arg (c.1882T>C) is classified Benign in ACTN3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-21). AlphaMissense: likely benign (0.023); Common (popmax 84.1%, afr) — too common for a highly-penetrant pathogenic allele; Associated with ACTN3-related disorder.

What condition is associated with ACTN3 p.Cys628Arg (c.1882T>C)?

ACTN3 p.Cys628Arg (c.1882T>C) is associated with ACTN3-related disorder (ClinVar).

What do computational predictors say about ACTN3 p.Cys628Arg (c.1882T>C)?

AlphaMissense predicts likely benign (score 0.023) — an in-silico prediction, not a clinical call.

ACTN3 p.Cys628Arg

Q: How common is ACTN3 p.Cys628Arg (c.1882T>C) in the general population?

ACTN3 p.Cys628Arg (c.1882T>C) is common (popmax 84.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1882T>C · rs618838 · VCV3059776

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.023 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 84.1%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Conditions

ACTN3-related disorder

Computational evidence

Protein change
AlphaMissense	0.023	likely benign
SaProt	LLR 3.21	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 4.9	GERP -2.5, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 7,830 bp · p 0.26 · regional, not allelic
Overall
CADD	18.36	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 84.1% African / African-American · 62,467/74,306 alleles

Filtering AF 83.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 83.3%

Overall 55.7% 882,982/1,586,418 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	84.1%	1
Finnishnot grpmax-eligible	67.4%	1
European (non-Finnish)	55.3%	2
Remaining individualsnot grpmax-eligible	55.3%	2
Middle Eastern	55.1%	2
Ashkenazi Jewishnot grpmax-eligible	54.7%	2
East Asian	51.2%	2
Amishnot grpmax-eligible	43.5%	2
South Asian	42.3%	2
Admixed American	37%	3

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.Cys628Arg
Coding: c.1882T>C
MANE Select: NM_001104
dbSNP: rs618838
Type: single nucleotide variant
Location: chr11:66561248 (GRCh38)
Gene constraint: LOEUF 0.944 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.61 · 3 PDB
Residue 628: a UniProt-annotated variant site (very low expression, if any, at the protein level in skeletal muscle); a UniProt-annotated variant site (in)

Full ACTN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ACTN3-related disorder

Similar variants

ACTN3 p.Cys628Tyr 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.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

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-cys628arg (accessed [today's date]).

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