Is CAPN3 p.Arg357Trp (c.1069C>T) pathogenic?

CAPN3 p.Arg357Trp (c.1069C>T) is classified Conflicting classifications of pathogenicity in CAPN3 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-05-13). AlphaMissense: likely pathogenic (0.7845); Very rare (popmax 0.00382%, amr); Associated with CAPN3-related disorder.

How common is CAPN3 p.Arg357Trp (c.1069C>T) in the general population?

CAPN3 p.Arg357Trp (c.1069C>T) is very rare (popmax 0.00382%, amr) (gnomAD).

What do computational predictors say about CAPN3 p.Arg357Trp (c.1069C>T)?

AlphaMissense predicts likely pathogenic (score 0.7845) — an in-silico prediction, not a clinical call.

CAPN3 p.Arg357Trp

Q: What condition is associated with CAPN3 p.Arg357Trp (c.1069C>T)?

CAPN3 p.Arg357Trp (c.1069C>T) is associated with CAPN3-related disorder, autosomal recessive limb-girdle muscular dystrophy type 2A, muscular dystrophy, limb-girdle, autosomal dominant 4 (ClinVar).

c.1069C>T · rs774273767 · VCV500723

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.7845 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00382%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CAPN3-related disorder

Computational evidence

Protein change
AlphaMissense	0.7845	likely pathogenic
REVEL	0.801	moderately pathogenic-leaning
SaProt	LLR -12.47	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.62 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4	GERP 2.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.21 · regional, not allelic
Overall
CADD	28.6	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 0.00382% Admixed American · 2/52,360 alleles

Filtering AF 0.000633% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000237%

Overall 0.000576% 9/1,563,212 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00382%	26,180
Remaining individualsnot grpmax-eligible	0.00165%	60,606
European (non-Finnish)	0.00052%	192,211

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.Arg357Trp
Coding: c.1069C>T
MANE Select: NM_000070
dbSNP: rs774273767
Type: single nucleotide variant
Location: chr15:42394295 (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 357: the calpain catalytic domain; a β-strand

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

Disease context

Also linked: autosomal recessive limb-girdle muscular dystrophy type 2A muscular dystrophy, limb-girdle, autosomal dominant 4

Similar variants

CAPN3 p.Arg357Gln Conflicting classifications of pathogenicity ★ ⚠ 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-arg357trp (accessed [today's date]).

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