CAPN3

Chr 15ADAR

calpain 3

Also known as: CANP3, CANPL3, LGMD2, LGMD2A, LGMDD4, LGMDR1, nCL-1, p94

NCBI Gene: 825ENSG00000092529UniProt: P20807

Calpain, a heterodimer consisting of a large and a small subunit, is a major intracellular protease, although its function has not been well established. This gene encodes a muscle-specific member of the calpain large subunit family that specifically binds to titin. Mutations in this gene are associated with limb-girdle muscular dystrophies type 2A. Alternate promoters and alternative splicing result in multiple transcript variants encoding different isoforms and some variants are ubiquitously expressed. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Muscular dystrophy, limb-girdle, autosomal dominant 4MIM #618129
AD
Muscular dystrophy, limb-girdle, autosomal recessive 1MIM #253600
AR
2150
ClinVar variants
93
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— CAPN3
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
93 Pathogenic / Likely Pathogenic· 205 VUS of 2150 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.96LOEUF
pLI 0.000
Z-score 1.75
OE 0.73 (0.56–0.96)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.03Z-score
OE missense 1.00 (0.93–1.08)
469 obs / 467.0 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.73 (0.56–0.96)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.00 (0.93–1.08)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.15
0≤1.21.6
LoF obs/exp: 36 / 49.2Missense obs/exp: 469 / 467.0Syn Z: -1.63

ClinVar Variant Classifications

2150 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic42
Likely Pathogenic51
VUS205
Likely Benign177
Benign3
Conflicting5
42
Pathogenic
51
Likely Pathogenic
205
VUS
177
Likely Benign
3
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
25
3
14
0
42
Likely Pathogenic
28
9
12
2
51
VUS
2
168
25
10
205
Likely Benign
0
0
124
53
177
Benign
0
0
3
0
3
Conflicting
—5
Total5518017865483

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

CAPN3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
CALPAIN 3; CAPN3
MIM #114240 · *

Muscular dystrophy, limb-girdle, autosomal dominant 4

MIM #618129

Molecular basis of disorder known

Autosomal dominant

Muscular dystrophy, limb-girdle, autosomal recessive 1

MIM #253600

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness.
Töpf A et al.·Genet Med
2020Cohort
Whole-exome sequencing identifies novel pathogenic mutations and putative phenotype-influencing variants in Polish limb-girdle muscular dystrophy patients.
Fichna JP et al.·Hum Genomics
2018Cohort
LGMD2A: genotype-phenotype correlations based on a large mutational survey on the calpain 3 gene.
Sáenz A et al.·Brain
2005
Autosomal recessive limb-girdle and Miyoshi muscular dystrophies in the Netherlands: The clinical and molecular spectrum of 244 patients.
Ten Dam L et al.·Clin Genet
2019Cohort
Calcium Mechanisms in Limb-Girdle Muscular Dystrophy with CAPN3 Mutations.
Lasa-Elgarresta J et al.·Int J Mol Sci
2019Review
Variants in CAPN3 Causing Autosomal Dominant Limb-Girdle Muscular Dystrophy Combined With Calpain-3 Deficiency.
Krag T et al.·Hum Mutat
2025
CAPN3 c.1746-20C>G variant is hypomorphic for LGMD R1 calpain 3-related.
Mroczek M et al.·Hum Mutat
2022
The CAPN3 p.Lys 254del variant is not always associated with dominant CAPN3-related muscular dystrophy.
Valls A et al.·Muscle Nerve
2024
Integrative variants, haplotypes and diplotypes of the CAPN3 and FRMD5 genes and several environmental exposures associate with serum lipid variables.
Guo T et al.·Sci Rep
2017
Clinical and Pathological Heterogeneity of Korean Patients with CAPN3 Mutations.
Park HJ et al.·Yonsei Med J
2016Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools