Muscular dystrophy, limb-girdle, autosomal dominant 4

Summary

Muscular dystrophy, limb-girdle, autosomal dominant 4 (MONDO:0029133) is a disease caused by CAPN3 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CAPN3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 298

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		47	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	muscular dystrophy, limb-girdle, autosomal dominant 4
Mondo ID	MONDO:0029133
OMIM	618129
Orphanet	565909
UMLS	C4748295
MedGen	1648316
GARD	0022272
Is cancer (heuristic)	no

Also known as: calpain-3-related LGMD D4 · calpain-3-related limb-girdle muscular dystrophy D4 · LGMD type D4 · LGMD1I · LGMDD4 · limb-girdle muscular dystrophy type D4 · muscular dystrophy, limb-girdle, autosomal dominant 4 · muscular dystrophy, limb-girdle, type 1I

Data availability: 298 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › muscular dystrophy, limb-girdle, autosomal dominant › muscular dystrophy, limb-girdle, autosomal dominant 4

Related subtypes (7): autosomal dominant limb-girdle muscular dystrophy type 1F, autosomal dominant limb-girdle muscular dystrophy type 1G, myofibrillar myopathy 3, autosomal dominant limb-girdle muscular dystrophy type 1H, autosomal dominant limb-girdle muscular dystrophy type 1E (DES), autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6), Emery-Dreifuss muscular dystrophy 2, autosomal dominant

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

298 retrieved; paginated sample, class counts are floors:

92 pathogenic, 60 pathogenic/likely pathogenic, 53 likely pathogenic, 41 uncertain significance, 38 conflicting classifications of pathogenicity, 8 benign, 5 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1067979	NM_000070.3(CAPN3):c.945+1G>T	CAPN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068777	NM_000070.3(CAPN3):c.433del (p.Leu145fs)	CAPN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069050	NM_000070.3(CAPN3):c.1788_1791del (p.Lys598fs)	CAPN3	Pathogenic	criteria provided, multiple submitters, no conflicts
1069199	NM_000070.3(CAPN3):c.60del (p.Pro22fs)	CAPN3	Pathogenic	criteria provided, multiple submitters, no conflicts
1285364	NM_000070.3(CAPN3):c.2257delinsAA (p.Asp753fs)	CAPN3	Pathogenic	criteria provided, single submitter
128569	NM_000070.3(CAPN3):c.2207_2208del (p.Thr736fs)	CAPN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
128570	NM_000070.3(CAPN3):c.2243G>A (p.Arg748Gln)	CAPN3	Pathogenic	reviewed by expert panel
1315302	NM_000070.3(CAPN3):c.379+3A>G	CAPN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1325395	NM_000070.3(CAPN3):c.966T>A (p.Tyr322Ter)	CAPN3	Pathogenic	criteria provided, multiple submitters, no conflicts
1325397	NM_000070.3(CAPN3):c.743T>G (p.Met248Arg)	CAPN3	Pathogenic	criteria provided, multiple submitters, no conflicts
1325402	NM_000070.3(CAPN3):c.616del (p.Glu206fs)	CAPN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1428600	NM_000070.3(CAPN3):c.2201del (p.Tyr734fs)	CAPN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
166786	NM_000070.3(CAPN3):c.598_612del (p.Phe200_Leu204del)	CAPN3	Pathogenic	reviewed by expert panel
166790	NM_000070.3(CAPN3):c.1468C>T (p.Arg490Trp)	CAPN3	Pathogenic	reviewed by expert panel
166791	NM_000070.3(CAPN3):c.1699G>T (p.Gly567Trp)	CAPN3	Pathogenic	criteria provided, multiple submitters, no conflicts
1701253	NM_000070.3(CAPN3):c.1469delinsTC (p.Arg490fs)	CAPN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17613	NM_000070.3(CAPN3):c.2306G>A (p.Arg769Gln)	CAPN3	Pathogenic	reviewed by expert panel
17614	NM_000070.3(CAPN3):c.1715G>A (p.Arg572Gln)	CAPN3	Pathogenic	reviewed by expert panel
17615	NM_000070.3(CAPN3):c.328C>T (p.Arg110Ter)	CAPN3	Pathogenic	reviewed by expert panel
17617	NM_000070.3(CAPN3):c.956C>T (p.Pro319Leu)	CAPN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17618	NM_000070.3(CAPN3):c.2362_2363delinsTCATCT (p.Arg788fs)	CAPN3	Pathogenic	reviewed by expert panel
17620	NM_000070.3(CAPN3):c.1795dup (p.Thr599fs)	CAPN3	Pathogenic	criteria provided, multiple submitters, no conflicts
17621	NM_000070.3(CAPN3):c.550del (p.Thr184fs)	CAPN3	Pathogenic	reviewed by expert panel
17622	NM_000070.3(CAPN3):c.1469G>A (p.Arg490Gln)	CAPN3	Pathogenic	reviewed by expert panel
193037	NM_000070.3(CAPN3):c.145C>T (p.Arg49Cys)	CAPN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
193792	NM_000070.3(CAPN3):c.1477C>T (p.Arg493Trp)	CAPN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
194691	NM_000070.3(CAPN3):c.1981del (p.Gln660_Ile661insTer)	CAPN3	Pathogenic	reviewed by expert panel
195450	NM_000070.3(CAPN3):c.2134C>T (p.Leu712Phe)	CAPN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
195641	NM_000070.3(CAPN3):c.2338G>C (p.Asp780His)	CAPN3	Pathogenic	criteria provided, multiple submitters, no conflicts
197624	NM_000070.3(CAPN3):c.756GAA[1] (p.Lys254del)	CAPN3	Pathogenic	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
CAPN3	Definitive	Autosomal recessive	autosomal recessive limb-girdle muscular dystrophy type 2A	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CAPN3	Orphanet:267	Calpain-3-related limb-girdle muscular dystrophy R1
CAPN3	Orphanet:565909	Calpain-3-related limb-girdle muscular dystrophy D4

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CAPN3	HGNC:1480	ENSG00000092529	P20807	Calpain-3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CAPN3	Calpain-3	Calcium-regulated non-lysosomal thiol-protease.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CAPN3	Protease	yes	3.4.22.54	Pept_cys_AS, Peptidase_C2_calpain_cat, EF_hand_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
C1 segment of cervical spinal cord	1
hindlimb stylopod muscle	1
skeletal muscle tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CAPN3	134	broad	marker	hindlimb stylopod muscle, skeletal muscle tissue, C1 segment of cervical spinal cord

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CAPN3	1,977

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CAPN3	P20807	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Degradation of the extracellular matrix	1	117.7×	0.016	CAPN3
Extracellular matrix organization	1	63.1×	0.016	CAPN3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
calcium-dependent self proteolysis	1	16852.0×	0.002	CAPN3
positive regulation of satellite cell activation involved in skeletal muscle regeneration	1	8426.0×	0.002	CAPN3
cellular response to salt stress	1	4213.0×	0.002	CAPN3
G1 to G0 transition involved in cell differentiation	1	2808.7×	0.002	CAPN3
regulation of myoblast differentiation	1	2407.4×	0.002	CAPN3
negative regulation of protein sumoylation	1	1532.0×	0.002	CAPN3
self proteolysis	1	1532.0×	0.002	CAPN3
muscle structure development	1	1404.3×	0.002	CAPN3
myofibril assembly	1	1123.5×	0.003	CAPN3
positive regulation of proteolysis	1	802.5×	0.003	CAPN3
muscle cell cellular homeostasis	1	648.1×	0.004	CAPN3
protein localization to membrane	1	601.9×	0.004	CAPN3
response to muscle activity	1	581.1×	0.004	CAPN3
positive regulation of release of sequestered calcium ion into cytosol	1	495.6×	0.004	CAPN3
regulation of canonical NF-kappaB signal transduction	1	481.5×	0.004	CAPN3
sarcomere organization	1	383.0×	0.004	CAPN3
response to calcium ion	1	318.0×	0.005	CAPN3
protein destabilization	1	290.6×	0.005	CAPN3
protein catabolic process	1	237.3×	0.006	CAPN3
cellular response to calcium ion	1	200.6×	0.007	CAPN3
muscle organ development	1	166.8×	0.008	CAPN3
protein-containing complex assembly	1	113.9×	0.011	CAPN3
negative regulation of apoptotic process	1	34.8×	0.033	CAPN3
proteolysis	1	34.2×	0.033	CAPN3
negative regulation of DNA-templated transcription	1	31.6×	0.034	CAPN3
apoptotic process	1	28.7×	0.036	CAPN3
positive regulation of DNA-templated transcription	1	27.9×	0.036	CAPN3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CAPN3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CAPN3	3.4.22.54, 3.4.22.56	calpain-3, caspase-3

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	CAPN3
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
CAPN3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.