Is ACTN3 p.Arg48Gln (c.143G>A) pathogenic?

ACTN3 p.Arg48Gln (c.143G>A) is classified Uncertain significance in ACTN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-14). AlphaMissense: likely benign (0.2663); Ultra-rare (popmax 0.011%, nfe).

How common is ACTN3 p.Arg48Gln (c.143G>A) in the general population?

ACTN3 p.Arg48Gln (c.143G>A) is ultra-rare (popmax 0.011%, nfe) (gnomAD).

What do computational predictors say about ACTN3 p.Arg48Gln (c.143G>A)?

AlphaMissense predicts likely benign (score 0.2663) — an in-silico prediction, not a clinical call.

ACTN3 p.Arg48Gln

c.143G>A · rs754278158 · VCV2471199

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2663 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt

Computational evidence

Protein change
AlphaMissense	0.2663	likely benign
SaProt	LLR -10.26	damaging
⇒ SaProt calls this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,650 bp · p 0.64 · regional, not allelic
Overall
CADD	33.0	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 0.011% European (non-Finnish) · 124/1,129,738 alleles

Filtering AF 0.00941% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00879%

Overall 0.0085% 128/1,505,064 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.011%	9,111
Remaining individualsnot grpmax-eligible	0.00521%	19,183
African / African-American	0.0014%	71,360

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.Arg48Gln
Coding: c.143G>A
MANE Select: NM_001104
dbSNP: rs754278158
Type: single nucleotide variant
Location: chr11:66547080 (GRCh38)
Gene constraint: LOEUF 0.944 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.61 · 3 PDB
Residue 48: 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.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-arg48gln (accessed [today's date]).

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