Is ACTN3 p.Leu81= (c.241C>T) pathogenic?

ACTN3 p.Leu81= (c.241C>T) is classified Likely benign in ACTN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-01). Rare (popmax 0.879%, nfe).

How common is ACTN3 p.Leu81= (c.241C>T) in the general population?

ACTN3 p.Leu81= (c.241C>T) is rare (popmax 0.879%, nfe) (gnomAD).

ACTN3 p.Leu81=

c.241C>T · rs187286120 · VCV2641991

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.879%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.24	GERP -1.5, phastCons 0.98
Overall
CADD	7.548	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.879% European (non-Finnish) · 10,347/1,177,376 alleles

Filtering AF 0.865% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.859%

Overall 0.771% 12,403/1,608,516 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.68%	60
Finnishnot grpmax-eligible	1.02%	98
European (non-Finnish)grpmax	0.879%	114
Remaining individualsnot grpmax-eligible	0.788%	127
South Asian	0.21%	476
Admixed American	0.193%	519
African / African-American	0.151%	663
Middle Eastern	0.033%	3,028
East Asian	0.00224%	44,700

Ashkenazi Jewish 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.Leu81=
Coding: c.241C>T
MANE Select: NM_001104
dbSNP: rs187286120
Type: single nucleotide variant
Location: chr11:66551332 (GRCh38)
Gene constraint: LOEUF 0.944 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.61 · 3 PDB
Residue 81: the calponin-homology (ch) 1 domain; an α-helix; the 'actin-binding' region

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

Similar variants

ACTN3 p.Pro81= Benign 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-leu81 (accessed [today's date]).

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