autosomal recessive limb-girdle muscular dystrophy type 2A

Summary

autosomal recessive limb-girdle muscular dystrophy type 2A (MONDO:0009675) is a disease caused by CAPN3 (GenCC Definitive), with 1 cohort gene and 5 clinical trials.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal gene: CAPN3 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 1,770
• Phenotypes (HPO): 21
• Clinical trials: 5

Clinical features

Epidemiology

Prevalence records

4 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	1	Europe	Validated
Point prevalence	1-9 / 1 000 000	0.6	United Kingdom	Validated
Point prevalence	1-9 / 100 000	4.8	Reunion	Validated
Point prevalence	1-9 / 100 000	1.65	Italy	Not yet validated

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO ID	Term	Frequency
HP:0003324	Generalized muscle weakness	Very frequent (80-99%)
HP:0001371	Flexion contracture	Frequent (30-79%)
HP:0002987	Elbow flexion contracture	Frequent (30-79%)
HP:0003089	Hamstring contractures	Frequent (30-79%)
HP:0003236	Elevated circulating creatine kinase concentration	Frequent (30-79%)
HP:0003306	Spinal rigidity	Frequent (30-79%)
HP:0003307	Hyperlordosis	Frequent (30-79%)
HP:0003560	Muscular dystrophy	Frequent (30-79%)
HP:0003691	Scapular winging	Frequent (30-79%)
HP:0003701	Proximal muscle weakness	Frequent (30-79%)
HP:0005879	Congenital finger flexion contractures	Frequent (30-79%)
HP:0006466	Ankle flexion contracture	Frequent (30-79%)
HP:0007340	Lower limb muscle weakness	Frequent (30-79%)
HP:0008946	Pelvic girdle amyotrophy	Frequent (30-79%)
HP:0008981	Calf muscle hypertrophy	Frequent (30-79%)
HP:0009060	Scapular muscle atrophy	Frequent (30-79%)
HP:0012037	Pectoralis amyotrophy	Frequent (30-79%)
HP:0030051	Tip-toe gait	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001239	Wrist flexion contracture	Occasional (5-29%)
HP:0003551	Difficulty climbing stairs	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive limb-girdle muscular dystrophy type 2A
Mondo ID	MONDO:0009675
MeSH	C535895
OMIM	253600
Orphanet	267
DOID	DOID:0110275
NCIT	C142079
SNOMED CT	715341003
UMLS	C1869123
MedGen	358391
GARD	0001057
Is cancer (heuristic)	no

Also known as: autosomal recessive limb-girdle muscular dystrophy caused by mutation in CAPN3 · autosomal recessive limb-girdle muscular dystrophy type 2A · calpainopathy · CAPN3 autosomal recessive limb-girdle muscular dystrophy · Leyden-Moebius muscular dystrophy · LGMD2 · LGMD2A · limb-girdle muscular dystrophy due to calpain deficiency · limb-girdle muscular dystrophy type 2 · limb-girdle muscular dystrophy type 2A · muscular dystrophy limb girdle type 2A, erb type · muscular dystrophy, limb-girdle, autosomal recessive 1 · muscular dystrophy, limb-girdle, type 2A · primary calpainopathy

Data availability: 1,770 ClinVar variants · 3 GenCC gene-disease records · 9 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › autosomal recessive limb-girdle muscular dystrophy › autosomal recessive limb-girdle muscular dystrophy type 2A

Related subtypes (31): epidermolysis bullosa simplex 5B, with muscular dystrophy, autosomal recessive limb-girdle muscular dystrophy type 2B, autosomal recessive limb-girdle muscular dystrophy type 2C, autosomal recessive limb-girdle muscular dystrophy type 2H, autosomal recessive limb-girdle muscular dystrophy type 2F, autosomal recessive limb-girdle muscular dystrophy type 2G, autosomal recessive limb-girdle muscular dystrophy type 2E, autosomal recessive limb-girdle muscular dystrophy type 2I, autosomal recessive limb-girdle muscular dystrophy type 2D, autosomal recessive limb-girdle muscular dystrophy type 2J, autosomal recessive limb-girdle muscular dystrophy type 2K, autosomal recessive limb-girdle muscular dystrophy type 2L, autosomal recessive limb-girdle muscular dystrophy type 2M, autosomal recessive limb-girdle muscular dystrophy type 2O, autosomal recessive limb-girdle muscular dystrophy type 2N, autosomal recessive limb-girdle muscular dystrophy type 2Q, autosomal recessive limb-girdle muscular dystrophy type 2P, autosomal recessive limb-girdle muscular dystrophy type 2T, autosomal recessive limb-girdle muscular dystrophy type R18, autosomal recessive limb-girdle muscular dystrophy type 2U, limb-girdle muscular dystrophy due to POMK deficiency, autosomal recessive limb-girdle muscular dystrophy type 2X, autosomal recessive limb-girdle muscular dystrophy type 2W, autosomal recessive limb-girdle muscular dystrophy type 2Y, autosomal recessive limb-girdle muscular dystrophy type 2R1, muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 8, muscular dystrophy, limb-girdle, autosomal recessive 23, muscular dystrophy, limb-girdle, autosomal recessive 26, muscular dystrophy, limb-girdle, autosomal recessive 27, muscular dystrophy, limb-girdle, autosomal recessive 28, muscular dystrophy, limb-girdle, autosomal recessive 29

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

600 retrieved; paginated sample, class counts are floors:

299 likely benign, 134 uncertain significance, 76 pathogenic, 34 likely pathogenic, 21 conflicting classifications of pathogenicity, 18 pathogenic/likely pathogenic, 10 benign/likely benign, 7 benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1067511	NM_000070.3(CAPN3):c.2380+1G>A	CAPN3	Pathogenic	criteria provided, multiple submitters, no conflicts
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
1068828	NM_000070.3(CAPN3):c.389G>A (p.Trp130Ter)	CAPN3	Pathogenic	criteria provided, single submitter
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
1069414	NM_000070.3(CAPN3):c.1985del (p.Ala662fs)	CAPN3	Pathogenic	criteria provided, single submitter
1071203	NM_000070.3(CAPN3):c.2048_2051del (p.Lys683fs)	CAPN3	Pathogenic	criteria provided, single submitter
1071335	NM_000070.3(CAPN3):c.1590dup (p.Lys531fs)	CAPN3	Pathogenic	criteria provided, single submitter
1071948	NM_000070.3(CAPN3):c.1999G>T (p.Glu667Ter)	CAPN3	Pathogenic	criteria provided, single submitter
1072494	NM_000070.3(CAPN3):c.1977_1978delinsCT (p.Lys659_Gln660delinsAsnTer)	CAPN3	Pathogenic	criteria provided, single submitter
1074226	NM_000070.3(CAPN3):c.1740_1743del (p.Ser581fs)	CAPN3	Pathogenic	criteria provided, single submitter
1075864	NM_000070.3(CAPN3):c.286C>T (p.Gln96Ter)	CAPN3	Pathogenic	criteria provided, single submitter
1076334	NC_000015.9:g.(?42701491)(42703981_?)del	CAPN3	Pathogenic	criteria provided, single submitter
1076819	NM_000070.3(CAPN3):c.2019dup (p.Lys674fs)	CAPN3	Pathogenic	criteria provided, single submitter
1192502	NM_000070.3(CAPN3):c.2217C>G (p.Ser739=)	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
1299546	NM_000070.3(CAPN3):c.1363T>C (p.Trp455Arg)	CAPN3	Pathogenic	criteria provided, single submitter
1315302	NM_000070.3(CAPN3):c.379+3A>G	CAPN3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1321461	NM_000070.3(CAPN3):c.347C>A (p.Ala116Asp)	CAPN3	Pathogenic	criteria provided, single submitter
1325393	NM_000070.3(CAPN3):c.212_214delinsGG (p.Lys71fs)	CAPN3	Pathogenic/Likely 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
1352662	NM_000070.3(CAPN3):c.1895_1913dup (p.Pro639fs)	CAPN3	Pathogenic	criteria provided, single submitter
1358312	NM_000070.3(CAPN3):c.2050+1G>C	CAPN3	Pathogenic	criteria provided, single submitter
1370170	NM_000070.3(CAPN3):c.193del (p.His65fs)	CAPN3	Pathogenic	criteria provided, single submitter
1376842	NM_000070.3(CAPN3):c.648C>G (p.Tyr216Ter)	CAPN3	Pathogenic	criteria provided, single submitter
1382408	NM_000070.3(CAPN3):c.1012_1013del (p.Val338fs)	CAPN3	Pathogenic	criteria provided, single submitter
1398928	NM_000070.3(CAPN3):c.1800+2T>C	CAPN3	Pathogenic	criteria provided, single submitter

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: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	4
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05230459	PHASE1/PHASE2	RECRUITING	A Study to Evaluate the Safety of AB-1003 (Previously LION-101) in Subjects With Genetic Confirmation of LGMD2I/R9 (Part1)
NCT05618080	Not specified	RECRUITING	LGMD R1 Natural History Study
NCT05989620	Not specified	RECRUITING	Long-Term Development of Muscular Dystrophy Outcome Assessments
NCT03488784	Not specified	COMPLETED	Natural History of Limb Girdle Muscular Dystrophy Type 2A and Type 2E
NCT04349566	Not specified	COMPLETED	Fast Troponin as a Biomarker to Assess Exercise-induced Muscle Damage in Muscle Diseases