Is CAPN3 p.Arg461His (c.1382G>A) pathogenic?

CAPN3 p.Arg461His (c.1382G>A) is classified Uncertain significance in CAPN3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-01-31). AlphaMissense: likely benign (0.162); Ultra-rare (popmax 0.0164%, mid); Associated with autosomal recessive limb-girdle muscular dystrophy.

What condition is associated with CAPN3 p.Arg461His (c.1382G>A)?

CAPN3 p.Arg461His (c.1382G>A) is associated with autosomal recessive limb-girdle muscular dystrophy, autosomal recessive limb-girdle muscular dystrophy type 2A (ClinVar).

How common is CAPN3 p.Arg461His (c.1382G>A) in the general population?

CAPN3 p.Arg461His (c.1382G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CAPN3 p.Arg461His (c.1382G>A)?

AlphaMissense predicts likely benign (score 0.162) — an in-silico prediction, not a clinical call.

CAPN3 p.Arg461His

c.1382G>A · rs767398783 · VCV645343

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.162 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive limb-girdle muscular dystrophy

Computational evidence

Protein change
AlphaMissense	0.162	likely benign
REVEL	0.802	moderately pathogenic-leaning
SaProt	LLR -10.74	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP -0.43, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.21 · regional, not allelic
Overall
CADD	34.0	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.00161% 26/1,613,988 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
South Asian	0.0022%	45,543
European (non-Finnish)	0.00178%	56,192
Admixed American	0.00167%	59,988
African / African-American	0.00134%	74,888

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: CAPN3
Protein: p.Arg461His
Coding: c.1382G>A
MANE Select: NM_000070
dbSNP: rs767398783
Type: single nucleotide variant
Location: chr15:42401668 (GRCh38)
Gene constraint: LOEUF 0.896 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 79.18 · 5 PDB
Residue 461: the 'domain iii' region

Full CAPN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive limb-girdle muscular dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive limb-girdle muscular dystrophy type 2A

Similar variants

CAPN3 p.Arg461= Likely benign ★ same residue
CAPN3 c.1115+5G>C Pathogenic ★★★ same condition
CAPN3 c.1194-2A>G Pathogenic ★★★ same condition
CAPN3 c.1194-9A>G Pathogenic ★★★ same condition
CAPN3 c.1746-20C>G Pathogenic ★★★ same condition
CAPN3 c.1993-1G>A Pathogenic ★★★ same condition
CAPN3 c.499-1G>A Pathogenic ★★★ same condition
CAPN3 p.Ala702Val Pathogenic ★★★ 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/capn3-p-arg461his (accessed [today's date]).

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