Is CAPN3 p.Pro359Leu (c.1076C>T) pathogenic?

CAPN3 p.Pro359Leu (c.1076C>T) is classified Likely pathogenic in CAPN3 (ClinVar, Expert panel, 7 submitters; last evaluated 2026-04-28). AlphaMissense: likely pathogenic (0.9836); Very rare (popmax 8.67e-05%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy.

What condition is associated with CAPN3 p.Pro359Leu (c.1076C>T)?

CAPN3 p.Pro359Leu (c.1076C>T) is associated with autosomal recessive limb-girdle muscular dystrophy, autosomal recessive limb-girdle muscular dystrophy type 2A, muscular dystrophy, limb-girdle, autosomal dominant 4 (ClinVar).

How common is CAPN3 p.Pro359Leu (c.1076C>T) in the general population?

CAPN3 p.Pro359Leu (c.1076C>T) is very rare (popmax 8.67e-05%, nfe) (gnomAD).

What do computational predictors say about CAPN3 p.Pro359Leu (c.1076C>T)?

AlphaMissense predicts likely pathogenic (score 0.9836) — an in-silico prediction, not a clinical call.

CAPN3 p.Pro359Leu

c.1076C>T · rs794727895 · VCV198690

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9836 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.67e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive limb-girdle muscular dystrophy

ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP

Likely Pathogenic for autosomal recessive limb-girdle muscular dystrophy. Applied ACMG criteria (verbatim):

PM2_Supporting PP4_Strong PP3 PM3

Curation rationale (ClinGen, verbatim)

The NM_000070.3: c.1076C>T variant in CAPN3 is a missense variant predicted to cause substitution of proline by leucine at amino acid 359 (p.Pro359Leu). This variant has been reported in at least 8 patients with clinical signs of LGMD, including in a homozygous state in at least 6 individuals (1.0 pt; PMID: 22926650, 17596655, 30564623; ClinVar SCV001524377.1, SCV001544778.3 internal data communication; LOVD CAPN3_000128) and in unconfirmed phase with a likely pathogenic variant in at least one individual (c.1256A>G p.(Asp419Gly), 0.25 pts, PMID: 30564623, LOVD Individual #00220445, GRASP-LGMD Consortium internal data communication) (PM3). At least one patient homozygous for this variant displayed progressive limb girdle muscle weakness and absent expression of calpain-3 in skeletal muscle, which is highly specific for CAPN3-related LGMD (PMID: 17596655; PP4_Strong). The highest population minor allele frequency in gnomAD v4.1.1 is 0.00001648 (1/60664 alleles) in the Remaining population, which is lower than the ClinGen LGMD VCEP threshold (<0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.955, which is above the threshold of 0.70, evidence that correlates with impact to CAPN3 function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (specifications v2.0.0; 04/28/2026): PM3, PP4_Strong, PM2_Supporting, PP3.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9836	likely pathogenic ✓ concordant with ClinVar
REVEL	0.955	strongly pathogenic-leaning
SaProt	LLR -14.33	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.21 · 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 8.67e-05% European (non-Finnish) · 1/1,153,474 alleles

Overall 0.000142% 2/1,411,530 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00165%	60,664
European (non-Finnish)grpmax	8.67e-05%	1,153,474

Remaining individuals 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: CAPN3
Protein: p.Pro359Leu
Coding: c.1076C>T
MANE Select: NM_000070
dbSNP: rs794727895
Type: single nucleotide variant
Location: chr15:42394302 (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 359: the calpain catalytic domain

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 muscular dystrophy, limb-girdle, autosomal dominant 4

Similar variants

CAPN3 p.Pro359= 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-pro359leu (accessed [today's date]).

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