Is CAPN3 p.Arg440Pro (c.1319G>C) pathogenic?

CAPN3 p.Arg440Pro (c.1319G>C) is classified Uncertain significance in CAPN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-27). AlphaMissense: likely pathogenic (0.9263); Ultra-rare (popmax 0.0308%, sas); Associated with autosomal recessive limb-girdle muscular dystrophy type 2A.

What condition is associated with CAPN3 p.Arg440Pro (c.1319G>C)?

CAPN3 p.Arg440Pro (c.1319G>C) is associated with autosomal recessive limb-girdle muscular dystrophy type 2A (ClinVar).

How common is CAPN3 p.Arg440Pro (c.1319G>C) in the general population?

CAPN3 p.Arg440Pro (c.1319G>C) is ultra-rare (popmax 0.0308%, sas) (gnomAD).

What do computational predictors say about CAPN3 p.Arg440Pro (c.1319G>C)?

AlphaMissense predicts likely pathogenic (score 0.9263) — an in-silico prediction, not a clinical call.

CAPN3 p.Arg440Pro

Q: How is Calpain-3-related limb-girdle muscular dystrophy R1 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1319G>C · VCV4745914

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9263 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0308%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive limb-girdle muscular dystrophy type 2A

Computational evidence

Protein change
AlphaMissense	0.9263	likely pathogenic
REVEL	0.879	moderately pathogenic-leaning
SaProt	LLR -11.21	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.36	donor loss, 5 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.21 · regional, not allelic
Overall
CADD	26.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0308% South Asian · 28/90,880 alleles

Filtering AF 0.0218% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0188%

Overall 0.00192% 31/1,611,116 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0308%	3,246
Remaining individualsnot grpmax-eligible	0.0016%	62,310
European (non-Finnish)	0.00017%	589,213

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.Arg440Pro
Coding: c.1319G>C
MANE Select: NM_000070
Type: single nucleotide variant
Location: chr15:42399617 (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 440: the 'domain iii' region; a UniProt-annotated variant site (in lgmdr1)

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

Disease context

autosomal recessive limb-girdle muscular dystrophy type 2A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Calpain-3-related limb-girdle muscular dystrophy R1 (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

CAPN3 p.Arg440Gln Likely pathogenic ★★★ ⚠ same residue
CAPN3 p.Arg440Trp Pathogenic/Likely pathogenic ★★ 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

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-arg440pro (accessed [today's date]).

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