Is ACTN3 p.Arg577Ter (c.1729C>T) pathogenic?

ACTN3 p.Arg577Ter (c.1729C>T) is classified Benign in ACTN3 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-02-16). Common (popmax 62.4%, amr) — too common for a highly-penetrant pathogenic allele.

ACTN3 p.Arg577Ter

Q: How common is ACTN3 p.Arg577Ter (c.1729C>T) in the general population?

ACTN3 p.Arg577Ter (c.1729C>T) is common (popmax 62.4%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1729C>T · rs1815739 · VCV18312

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Common

common (popmax 62.4%, amr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 15 of 21
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.26	GERP -4, phastCons 0.094
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 62.4% Admixed American · 37,426/59,986 alleles

Filtering AF 61.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 61.6%

Overall 43.9% 708,445/1,613,426 alleles · common exomes 651,404/1,461,372 · genomes 57,041/152,054 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	62.4%	2
South Asian	57.3%	2
Amishnot grpmax-eligible	56.6%	2
East Asian	48.4%	2
Middle Eastern	46.1%	2
Ashkenazi Jewishnot grpmax-eligible	45%	2
Remaining individualsnot grpmax-eligible	44.1%	2
European (non-Finnish)	44.1%	2
Finnishnot grpmax-eligible	32.2%	3
African / African-American	16.4%	6

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.Arg577Ter
Coding: c.1729C>T
MANE Select: NM_001104
dbSNP: rs1815739
Type: single nucleotide variant
Location: chr11:66560624 (GRCh38)
Gene constraint: LOEUF 0.944 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.61 · 3 PDB
Residue 577: 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-arg577ter (accessed [today's date]).

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