Autosomal recessive limb-girdle muscular dystrophy

Summary

Autosomal recessive limb-girdle muscular dystrophy (MONDO:0015152) is a disease (an umbrella term covering 32 Mondo subtypes) caused by variants in DYSF, HMGCR, SGCA, and 3 other genes, with 17 cohort genes. The dominant Reactome pathway is DAG1 core M1 glycosylations (3 cohort genes).

At a glance

• Causal genes: DYSF (GenCC Strong), HMGCR (GenCC Strong), SGCA (GenCC Strong), SGCB (GenCC Strong) (+2 more)
• Umbrella term: 32 Mondo subtypes
• Cohort genes: 17
• ClinVar variants: 580

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive limb-girdle muscular dystrophy
Mondo ID	MONDO:0015152
MeSH	C538640
OMIM	253600
Orphanet	102015
DOID	DOID:0110274
ICD-11	319162980
UMLS	C2931907
MedGen	419194
GARD	0019825
Is cancer (heuristic)	no

Also known as: autosomal recessive limb-girdle muscular dystrophy · limb-girdle muscular dystrophy, autosomal recessive · muscular dystrophy, limb-girdle, autosomal recessive

Data availability: 580 ClinVar variants · 427 ClinGen variant curations · 6 GenCC gene-disease records.

Disease family

An umbrella term covering 32 Mondo subtypes.

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

Related subtypes (218): immunodeficiency-centromeric instability-facial anomalies syndrome, hypercalcemia, infantile, Ochoa syndrome, autosomal recessive Ehlers-Danlos syndrome, vascular type, hydrolethalus syndrome, 3-M syndrome, isolated hyperchlorhidrosis, dacryocystitis-osteopoikilosis syndrome, Hutchinson-Gilford progeria syndrome, achalasia microcephaly syndrome, acrorenal syndrome, autosomal recessive, beta-ketothiolase deficiency, autosomal recessive Alport syndrome, Alstrom syndrome, microphthalmia with limb anomalies, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, Behr syndrome, bifid nose, autosomal recessive, Bloom syndrome, Bowen-Conradi syndrome, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, heart defects-limb shortening syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, COFS syndrome, craniometaphyseal dysplasia, autosomal recessive, Fraser syndrome, cystic fibrosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, persistent hyperplastic primary vitreous, autosomal recessive, Donnai-Barrow syndrome, Schöpf-Schulz-Passarge syndrome, cleft lip/palate-ectodermal dysplasia syndrome, Ellis-van Creveld syndrome, Wolcott-Rallison syndrome, autosomal recessive faciodigitogenital syndrome, acromesomelic dysplasia 2B, brittle cornea syndrome, triple-A syndrome, autosomal recessive humeroradial synostosis, multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome, hydrocephalus, nonsyndromic, autosomal recessive 1, autosomal recessive hydrocephalus due to congenital stenosis of aqueduct of Sylvius, hypertelorism, microtia, facial clefting syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, Vici syndrome, Johanson-Blizzard syndrome, autosomal recessive Kenny-Caffey syndrome, Papillon-Lefevre disease, Haim-Munk syndrome, Laurence-Moon syndrome, Donohue syndrome, lipase deficiency, combined, autosomal recessive familial Mediterranean fever, thiamine-responsive megaloblastic anemia syndrome, cartilage-hair hypoplasia, Nijmegen breakage syndrome, pseudo-TORCH syndrome, Galloway-Mowat syndrome, mulibrey nanism, myotonia congenita, autosomal recessive, Schwartz-Jampel syndrome, proteosome-associated autoinflammatory syndrome, Netherton syndrome, Niemann-Pick disease type A, oculodentodigital dysplasia, autosomal recessive, odonto-onycho-dermal dysplasia, autosomal recessive omodysplasia, osteoporosis-pseudoglioma syndrome, Shwachman-Diamond syndrome, phenylketonuria, Bjornstad syndrome, Laron syndrome, autosomal recessive polycystic kidney disease, autosomal recessive inherited pseudoxanthoma elasticum, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, short-rib thoracic dysplasia 9 with or without polydactyly, autosomal recessive Robinow syndrome, Sjogren-Larsson syndrome, scapuloperoneal spinal muscular atrophy, autosomal recessive, spondyloepiphyseal dysplasia tarda, autosomal recessive, inherited threoninemia, Pendred syndrome, autosomal recessive spondylocostal dysostosis, Werner syndrome, ABCD syndrome, Naxos disease, autosomal recessive amelia, human HOXA1 syndromes, sickle cell disease, autosomal recessive proximal renal tubular acidosis, hyper-IgM syndrome type 2, temtamy preaxial brachydactyly syndrome, TH-deficient dopa-responsive dystonia, craniosynostosis syndrome, autosomal recessive, Niemann-Pick disease type B, skin fragility-woolly hair-palmoplantar keratoderma syndrome, CoQ-responsive OXPHOS deficiency, familial adenomatous polyposis 2, Pierson syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, cardiomyopathy-hypotonia-lactic acidosis syndrome, PHARC syndrome, Kahrizi syndrome, cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies, congenital prothrombin deficiency, immunodeficiency 31B, dyskeratosis congenita, autosomal recessive 2, dyskeratosis congenita, autosomal recessive 3, Nestor-Guillermo progeria syndrome, leukoencephalopathy with calcifications and cysts, mitochondrial pyruvate carrier deficiency, branched-chain keto acid dehydrogenase kinase deficiency, dyskeratosis congenita, autosomal recessive 5, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, alacrima, achalasia, and intellectual disability syndrome, hyperlipoproteinemia, type 1D, microcephaly and chorioretinopathy 2, congenital stationary night blindness 1G, combined oxidative phosphorylation deficiency 29, hypermanganesemia with dystonia 2, growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy, gnb5-related intellectual disability-cardiac arrhythmia syndrome, autosomal recessive spastic paraplegia type 78, Bardet-Biedl syndrome, autosomal recessive cerebellar ataxia, neuronopathy, distal hereditary motor, autosomal recessive, UV-sensitive syndrome, Ehlers-Danlos syndrome, kyphoscoliotic type 1, Cockayne syndrome, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, leukoencephalopathy-palmoplantar keratoderma syndrome, autosomal recessive hypohidrotic ectodermal dysplasia, Warburg micro syndrome, autosomal recessive primary microcephaly, autosomal recessive progressive external ophthalmoplegia, Meier-Gorlin syndrome, autosomal recessive sideroblastic anemia, autosomal recessive intermediate Charcot-Marie-Tooth disease, Perrault syndrome, autosomal recessive hypophosphatemic rickets, de Barsy syndrome, leukocyte adhesion deficiency, Senior-Loken syndrome, autosomal recessive spastic ataxia, childhood-onset autosomal recessive myopathy with external ophthalmoplegia, autosomal recessive cerebral atrophy, GM3 synthase deficiency, autosomal recessive distal renal tubular acidosis, pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome, autosomal recessive brachyolmia, Aicardi-Goutieres syndrome, homocystinuria without methylmalonic aciduria, Niemann-Pick disease type C, nephronophthisis, autosomal recessive osteopetrosis, peroxisome biogenesis disorder, congenital non-bullous ichthyosiform erythroderma, Seckel syndrome, Usher syndrome, autosomal recessive cutis laxa type 1, autosomal recessive cutis laxa type 2, hearing loss, autosomal recessive, microcephaly, growth restriction, and increased sister chromatid exchange 2, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1, congenital vertebral-cardiac-renal anomalies syndrome, hair defect with photosensitivity and intellectual disability syndrome, autosomal recessive severe congenital neutropenia, severe combined immunodeficiency due to CARMIL2 deficiency, extraoral halitosis due to methanethiol oxidase deficiency, neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, mitochondrial complex 2 deficiency, nuclear type 3, mitochondrial complex 2 deficiency, nuclear type 4, mismatch repair cancer syndrome, spondyloepimetaphyseal dysplasia with joint laxity, type 3, Kilquist syndrome, Duane anomaly-myopathy-scoliosis syndrome, autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, congenital myopathy with reduced type 2 muscle fibers, NAD(P)HX dehydratase deficiency, autosomal recessive ocular albinism, ichthyosis linearis circumflexa, eosinophil peroxidase deficiency, hyperphenylalaninemia due to DNAJC12 deficiency, autosomal recessive epidermolytic ichthyosis, Ehlers-Danlos syndrome, classic-like, 2, joint laxity, short stature, and myopia, HELIX syndrome, auditory neuropathy-optic atrophy syndrome, glycosylphosphatidylinositol biosynthesis defect 15, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, SCN4A-related myopathy, autosomal recessive, Uner Tan Syndrome, nephropathic cystinosis, Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome type 2, permanent neonatal diabetes mellitus 1, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, Rajab interstitial lung disease with brain calcifications 1, Roberts-SC phocomelia syndrome, neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, RPE65-related recessive retinopathy, GUCY2D-related recessive retinopathy, autosomal recessive titinopathy, intellectual disability, autosomal recessive, ALPL-related autosomal recessive hypophosphatasia, spastic paraplegia 18b, autosomal recessive, CEP164-related ciliopathy, RP1-related recessive retinopathy, pseudohypoaldosteronism, type IB2, autosomal recessive, pseudohypoaldosteronism, type IB3, autosomal recessive, spastic paraplegia 30B, autosomal recessive, cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, brain small vessel disease 2B, autosomal recessive, IMPG1-related recessive retinopathy, PROM1-related recessive retinopathy

Subtypes (32): epidermolysis bullosa simplex 5B, with muscular dystrophy, autosomal recessive limb-girdle muscular dystrophy type 2A, 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

580 retrieved; paginated sample, class counts are floors:

278 pathogenic, 82 likely pathogenic, 79 pathogenic/likely pathogenic, 38 uncertain significance, 36 benign, 36 conflicting classifications of pathogenicity, 31 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
140553	NM_213599.3(ANO5):c.1733T>C (p.Phe578Ser)	ANO5	Pathogenic	reviewed by expert panel
140555	NM_213599.3(ANO5):c.2018A>G (p.Tyr673Cys)	ANO5	Pathogenic	reviewed by expert panel
194577	NM_213599.3(ANO5):c.1520del (p.Phe507fs)	ANO5	Pathogenic	criteria provided, multiple submitters, no conflicts
194805	NM_213599.3(ANO5):c.1898+1G>A	ANO5	Pathogenic	reviewed by expert panel
197402	NM_213599.3(ANO5):c.172C>T (p.Arg58Trp)	ANO5	Pathogenic	reviewed by expert panel
197908	NM_213599.3(ANO5):c.201_205del (p.Ser67fs)	ANO5	Pathogenic	criteria provided, multiple submitters, no conflicts
2142171	NM_213599.3(ANO5):c.431_432del (p.Ala144fs)	ANO5	Pathogenic	criteria provided, multiple submitters, no conflicts
2163	NM_213599.3(ANO5):c.1295C>G (p.Ala432Gly)	ANO5	Pathogenic	reviewed by expert panel
2164	NM_213599.3(ANO5):c.191dup (p.Asn64fs)	ANO5	Pathogenic	reviewed by expert panel
2166	NM_213599.3(ANO5):c.2272C>T (p.Arg758Cys)	ANO5	Pathogenic	reviewed by expert panel
280322	NM_213599.3(ANO5):c.304_308del (p.Lys102fs)	ANO5	Pathogenic	reviewed by expert panel
282394	NM_213599.3(ANO5):c.1640G>A (p.Arg547Gln)	ANO5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
285338	NM_213599.3(ANO5):c.2498T>A (p.Met833Lys)	ANO5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
285669	NM_213599.3(ANO5):c.2004del (p.Leu669fs)	ANO5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
288833	NM_213599.3(ANO5):c.108_109del (p.Glu36fs)	ANO5	Pathogenic	reviewed by expert panel
3338962	NM_213599.3(ANO5):c.986T>G (p.Leu329Ter)	ANO5	Pathogenic	criteria provided, single submitter
468825	NM_213599.3(ANO5):c.148C>T (p.Arg50Ter)	ANO5	Pathogenic	reviewed by expert panel
468837	NM_213599.3(ANO5):c.1963T>C (p.Trp655Arg)	ANO5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
523571	NM_213599.3(ANO5):c.1965G>C (p.Trp655Cys)	ANO5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
536726	NM_213599.3(ANO5):c.1120-1G>A	ANO5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
596409	NM_213599.3(ANO5):c.835C>T (p.Arg279Ter)	ANO5	Pathogenic	criteria provided, multiple submitters, no conflicts
96679	NM_213599.3(ANO5):c.242A>G (p.Asp81Gly)	ANO5	Pathogenic	reviewed by expert panel
96685	NM_213599.3(ANO5):c.41-1G>A	ANO5	Pathogenic	reviewed by expert panel
96688	NM_213599.3(ANO5):c.989dup (p.Leu330fs)	ANO5	Pathogenic	reviewed by expert panel
972625	NM_012210.4(TRIM32):c.458_465del (p.Leu153fs)	ASTN2	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
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
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

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 32 · Orphanet: 49 · 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
SGCA	Definitive	Autosomal recessive	autosomal recessive limb-girdle muscular dystrophy type 2D	5
SGCB	Definitive	Autosomal recessive	autosomal recessive limb-girdle muscular dystrophy type 2E	5
SGCD	Definitive	Autosomal recessive	autosomal recessive limb-girdle muscular dystrophy type 2F	7
SGCG	Definitive	Autosomal recessive	autosomal recessive limb-girdle muscular dystrophy type 2C	5
DYSF	Strong	Autosomal recessive	autosomal recessive limb-girdle muscular dystrophy type 2B	7
HMGCR	Strong	Autosomal recessive	muscular dystrophy, limb-girdle, autosomal recessive 28	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SGCA	Orphanet:62	Alpha-sarcoglycan-related limb-girdle muscular dystrophy R3
SGCB	Orphanet:119	Beta-sarcoglycan-related limb-girdle muscular dystrophy R4
SGCD	Orphanet:154	Familial isolated dilated cardiomyopathy
SGCD	Orphanet:219	Delta-sarcoglycan-related limb-girdle muscular dystrophy R6
SGCG	Orphanet:353	Gamma-sarcoglycan-related limb-girdle muscular dystrophy R5
DYSF	Orphanet:178400	Distal myopathy with anterior tibial onset
DYSF	Orphanet:199329	Congenital myopathy, Paradas type
DYSF	Orphanet:268	Dysferlin-related limb-girdle muscular dystrophy R2
DYSF	Orphanet:45448	Miyoshi myopathy
HMGCR	Orphanet:653725	Autosomal recessive limb-girdle muscular dystrophy, type 28
CAPN3	Orphanet:267	Calpain-3-related limb-girdle muscular dystrophy R1
CAPN3	Orphanet:565909	Calpain-3-related limb-girdle muscular dystrophy D4
TRIM32	Orphanet:110	Bardet-Biedl syndrome
TRIM32	Orphanet:1878	TRIM32-related limb-girdle muscular dystrophy R8
FKRP	Orphanet:34515	FKRP-related limb-girdle muscular dystrophy R9
FKRP	Orphanet:370959	Congenital muscular dystrophy with cerebellar involvement
FKRP	Orphanet:370968	Congenital muscular dystrophy with intellectual disability
FKRP	Orphanet:370980	Congenital muscular dystrophy without intellectual disability
FKRP	Orphanet:588	Muscle-eye-brain disease
FKRP	Orphanet:899	Walker-Warburg syndrome
POMGNT1	Orphanet:206564	POMGNT1-related limb-girdle muscular dystrophy R15
POMGNT1	Orphanet:370959	Congenital muscular dystrophy with cerebellar involvement
POMGNT1	Orphanet:588	Muscle-eye-brain disease
POMGNT1	Orphanet:791	Retinitis pigmentosa
POMGNT1	Orphanet:899	Walker-Warburg syndrome
POMT2	Orphanet:206559	POMT2-related limb-girdle muscular dystrophy R14
POMT2	Orphanet:370959	Congenital muscular dystrophy with cerebellar involvement
POMT2	Orphanet:370968	Congenital muscular dystrophy with intellectual disability
POMT2	Orphanet:588	Muscle-eye-brain disease
POMT2	Orphanet:899	Walker-Warburg syndrome
TRAPPC11	Orphanet:369840	TRAPPC11-related limb-girdle muscular dystrophy R18
TRAPPC11	Orphanet:369847	Intellectual disability-hyperkinetic movement-truncal ataxia syndrome
TRAPPC11	Orphanet:869	Triple A syndrome
ANO5	Orphanet:206549	Anoctamin-5-related limb-girdle muscular dystrophy R12
ANO5	Orphanet:206599	Isolated asymptomatic elevation of creatine phosphokinase
ANO5	Orphanet:399096	Distal anoctaminopathy
ANO5	Orphanet:53697	Gnathodiaphyseal dysplasia
ANO5	Orphanet:689021	Asymptomatic hyperCKemia-myalgia-rhabdomyolysis syndrome
PLEC	Orphanet:1114	Aplasia cutis congenita
PLEC	Orphanet:158684	Epidermolysis bullosa simplex with pyloric atresia
PLEC	Orphanet:254361	Plectin-related limb-girdle muscular dystrophy R17
PLEC	Orphanet:257	Epidermolysis bullosa simplex with muscular dystrophy
PLEC	Orphanet:79401	PLEC-related intermediate epidermolysis bullosa simplex without extracutaneous involvement
POMT1	Orphanet:370959	Congenital muscular dystrophy with cerebellar involvement
POMT1	Orphanet:370968	Congenital muscular dystrophy with intellectual disability
POMT1	Orphanet:370980	Congenital muscular dystrophy without intellectual disability
POMT1	Orphanet:588	Muscle-eye-brain disease
POMT1	Orphanet:86812	POMT1-related limb-girdle muscular dystrophy R11
POMT1	Orphanet:899	Walker-Warburg syndrome

Cohort genes → proteins

17 cohort genes, 17 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	17

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SGCA	HGNC:10805	ENSG00000108823	Q16586	Alpha-sarcoglycan	gencc,clinvar
SGCB	HGNC:10806	ENSG00000163069	Q16585	Beta-sarcoglycan	gencc,clinvar
SGCD	HGNC:10807	ENSG00000170624	Q92629	Delta-sarcoglycan	gencc,clinvar
SGCG	HGNC:10809	ENSG00000102683	Q13326	Gamma-sarcoglycan	gencc,clinvar
DYSF	HGNC:3097	ENSG00000135636	O75923	Dysferlin	gencc,clinvar
HMGCR	HGNC:5006	ENSG00000113161	P04035	3-hydroxy-3-methylglutaryl-coenzyme A reductase	gencc
CAPN3	HGNC:1480	ENSG00000092529	P20807	Calpain-3	clinvar
TRIM32	HGNC:16380	ENSG00000119401	Q13049	E3 ubiquitin-protein ligase TRIM32	clinvar
ASTN2	HGNC:17021	ENSG00000148219	O75129	Astrotactin-2	clinvar
FKRP	HGNC:17997	ENSG00000181027	Q9H9S5	Ribitol 5-phosphate transferase FKRP	clinvar
POMGNT1	HGNC:19139	ENSG00000085998	Q8WZA1	Protein O-linked-mannose beta-1,2-N-acetylglucosaminyltransferase 1	clinvar
POMT2	HGNC:19743	ENSG00000009830	Q9UKY4	Protein O-mannosyl-transferase 2	clinvar
TSPAN1	HGNC:20657	ENSG00000117472	O60635	Tetraspanin-1	clinvar
TRAPPC11	HGNC:25751	ENSG00000168538	Q7Z392	Trafficking protein particle complex subunit 11	clinvar
ANO5	HGNC:27337	ENSG00000171714	Q75V66	Anoctamin-5	clinvar
PLEC	HGNC:9069	ENSG00000178209	Q15149	Plectin	clinvar
POMT1	HGNC:9202	ENSG00000130714	Q9Y6A1	Protein O-mannosyl-transferase 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SGCA	Alpha-sarcoglycan	Component of the sarcoglycan complex, a subcomplex of the dystrophin-glycoprotein complex which forms a link between the F-actin cytoskeleton and the extracellular matrix.
SGCB	Beta-sarcoglycan	Component of the sarcoglycan complex, a subcomplex of the dystrophin-glycoprotein complex which forms a link between the F-actin cytoskeleton and the extracellular matrix.
SGCD	Delta-sarcoglycan	Component of the sarcoglycan complex, a subcomplex of the dystrophin-glycoprotein complex which forms a link between the F-actin cytoskeleton and the extracellular matrix.
SGCG	Gamma-sarcoglycan	Component of the sarcoglycan complex, a subcomplex of the dystrophin-glycoprotein complex which forms a link between the F-actin cytoskeleton and the extracellular matrix.
DYSF	Dysferlin	Key calcium ion sensor involved in the Ca(2+)-triggered synaptic vesicle-plasma membrane fusion.
HMGCR	3-hydroxy-3-methylglutaryl-coenzyme A reductase	Catalyzes the conversion of (3S)-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to mevalonic acid, the rate-limiting step in the synthesis of cholesterol and other isoprenoids, thus plays a critical role in cellular cholesterol homeostasis.
CAPN3	Calpain-3	Calcium-regulated non-lysosomal thiol-protease.
TRIM32	E3 ubiquitin-protein ligase TRIM32	E3 ubiquitin ligase that plays a role in various biological processes including neural stem cell differentiation, innate immunity, inflammatory resonse and autophagy.
ASTN2	Astrotactin-2	Mediates recycling of the neuronal cell adhesion molecule ASTN1 to the anterior pole of the cell membrane in migrating neurons.
FKRP	Ribitol 5-phosphate transferase FKRP	Catalyzes the transfer of a ribitol 5-phosphate from CDP-L-ribitol to the ribitol 5-phosphate previously attached by FKTN/fukutin to the phosphorylated O-mannosyl trisaccharide (N-acetylgalactosamine-beta-3-N-acetylglucosamine-beta-4-(phos…
POMGNT1	Protein O-linked-mannose beta-1,2-N-acetylglucosaminyltransferase 1	Participates in O-mannosyl glycosylation by catalyzing the addition of N-acetylglucosamine to O-linked mannose on glycoproteins.
POMT2	Protein O-mannosyl-transferase 2	Transfers mannosyl residues to the hydroxyl group of serine or threonine residues.
TSPAN1	Tetraspanin-1	Structural component of specialized membrane microdomains known as tetraspanin-enriched microdomains (TERMs), which act as platforms for receptor clustering and signaling.
TRAPPC11	Trafficking protein particle complex subunit 11	Involved in endoplasmic reticulum to Golgi apparatus trafficking at a very early stage.
ANO5	Anoctamin-5	Plays a role in plasma membrane repair in a process involving annexins.
PLEC	Plectin	Interlinks intermediate filaments with microtubules and microfilaments and anchors intermediate filaments to desmosomes or hemidesmosomes.
POMT1	Protein O-mannosyl-transferase 1	Transfers mannosyl residues to the hydroxyl group of serine or threonine residues.

Protein-family classification

Druggable: 6 · Difficult: 2 · Unknown: 9 · Druggable fraction: 0.35

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
Complement	1	15.8×	0.185
Enzyme (other)	4	2.8×	0.185
Protease	1	2.1×	0.751
Scaffold/PPI	1	1.0×	0.825
Other/Unknown	9	0.9×	0.825
Transcription factor	1	0.5×	0.889

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SGCA	Other/Unknown	no		Cadg, Sarcoglycan_alpha/epsilon, Cadherin-like_sf
SGCB	Other/Unknown	no		Sarcoglycan, Sgcb
SGCD	Other/Unknown	no		Sarcoglycan, Sarcoglycan_gamma/delta/zeta
SGCG	Other/Unknown	no		Sarcoglycan, Sarcoglycan_gamma/delta/zeta
DYSF	Other/Unknown	no		C2_dom, Peroxin/Ferlin, Ferlin_A-domain
HMGCR	Enzyme (other)	yes	1.1.1.34	SSD, HMG_CoA_Rdtase, HMG_CoA_Rdtase_eu_arc
CAPN3	Protease	yes	3.4.22.54	Pept_cys_AS, Peptidase_C2_calpain_cat, EF_hand_dom
TRIM32	Transcription factor	no		Znf_B-box, NHL_repeat, Znf_RING
ASTN2	Complement	yes		MACPF, Astrotactin, FN3_sf
FKRP	Other/Unknown	no		LicD/FKTN/FKRP_NTP_transf, LicD_transferase, FKRP_N
POMGNT1	Enzyme (other)	yes	2.4.1.312	Glyco_trans_13, Nucleotide-diphossugar_trans, POMGNT1_PANDER-like
POMT2	Enzyme (other)	yes	2.4.1.109	ArnT-like_N, MIR_motif, PMT-like
TSPAN1	Other/Unknown	no		Tetraspanin_animals, Tetraspanin_EC2_sf, Tetraspanin/Peripherin
TRAPPC11	Other/Unknown	no		TPC11, TRAPPC11_C
ANO5	Other/Unknown	no		Anoctamin, Anoct_dimer, Anoctamin_TM
PLEC	Scaffold/PPI	no		Plectin_repeat, SH3_domain, Actinin_actin-bd_CS
POMT1	Enzyme (other)	yes	2.4.1.109	ArnT-like_N, MIR_motif, PMT-like

Expression context

Cohort genes with no expression data: 0.

15 cohort genes 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)	17
unknown	0

Top tissues across cohort

Tissue	Cohort genes
hindlimb stylopod muscle	5
skeletal muscle tissue of rectus abdominis	4
left ventricle myocardium	3
apex of heart	2
gastrocnemius	2
adrenal tissue	2
C1 segment of cervical spinal cord	2
cardiac muscle of right atrium	2
skeletal muscle tissue of biceps brachii	1
tendon of biceps brachii	1
heart right ventricle	1
gluteal muscle	1
triceps brachii	1
blood	1
cortical plate	1
ventricular zone	1
skeletal muscle tissue	1
stromal cell of endometrium	1
tibialis anterior	1
buccal mucosa cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SGCA	190	broad	marker	hindlimb stylopod muscle, gastrocnemius, apex of heart
SGCB	288	ubiquitous	marker	tendon of biceps brachii, skeletal muscle tissue of rectus abdominis, skeletal muscle tissue of biceps brachii
SGCD	247	broad	marker	left ventricle myocardium, skeletal muscle tissue of rectus abdominis, heart right ventricle
SGCG	184	broad	marker	skeletal muscle tissue of rectus abdominis, gluteal muscle, triceps brachii
DYSF	257	ubiquitous	marker	blood, hindlimb stylopod muscle, skeletal muscle tissue of rectus abdominis
HMGCR	286	ubiquitous	marker	adrenal tissue, ventricular zone, cortical plate
CAPN3	134	broad	marker	hindlimb stylopod muscle, skeletal muscle tissue, C1 segment of cervical spinal cord
TRIM32	252	ubiquitous	yes	stromal cell of endometrium, tibialis anterior, gastrocnemius
ASTN2	236	ubiquitous	marker	buccal mucosa cell, trigeminal ganglion, dorsal root ganglion
FKRP	230	ubiquitous	marker	left ventricle myocardium, cardiac muscle of right atrium, hindlimb stylopod muscle
POMGNT1	269	ubiquitous	marker	apex of heart, C1 segment of cervical spinal cord, adenohypophysis
POMT2	222	ubiquitous	yes	right testis, left testis, testis
TSPAN1	206	broad	marker	bronchial epithelial cell, epithelium of bronchus, mucosa of transverse colon
TRAPPC11	277	ubiquitous	marker	calcaneal tendon, adrenal tissue, primordial germ cell in gonad
ANO5	220	broad	marker	cardiac muscle of right atrium, left ventricle myocardium, vastus lateralis
PLEC	283	ubiquitous	marker	sural nerve, hindlimb stylopod muscle, tibial nerve
POMT1	264	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 40.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HMGCR	5,062
PLEC	3,529
TRIM32	2,322
CAPN3	1,977
DYSF	1,776
ASTN2	1,610
POMT1	1,475
TRAPPC11	1,442
FKRP	1,436
POMT2	1,284

Intra-cohort edges

A	B	Sources
ANO5	DYSF	string_interaction
ANO5	FKRP	string_interaction
ANO5	POMGNT1	string_interaction
ANO5	POMT1	string_interaction
ANO5	POMT2	string_interaction
ANO5	SGCA	string_interaction
ANO5	SGCB	string_interaction
ANO5	SGCD	string_interaction
ANO5	SGCG	string_interaction
ANO5	TRIM32	string_interaction
CAPN3	DYSF	string_interaction
CAPN3	FKRP	string_interaction
CAPN3	SGCB	string_interaction
CAPN3	SGCG	string_interaction
CAPN3	TRIM32	string_interaction
DYSF	FKRP	string_interaction
DYSF	SGCA	string_interaction
DYSF	SGCB	string_interaction
DYSF	SGCD	string_interaction
DYSF	SGCG	biogrid_interaction, intact, string_interaction
FKRP	POMGNT1	string_interaction
FKRP	POMT1	string_interaction
FKRP	POMT2	string_interaction
FKRP	SGCA	string_interaction
FKRP	SGCB	string_interaction
FKRP	SGCG	string_interaction
FKRP	TRIM32	string_interaction
POMGNT1	POMT1	string_interaction
POMGNT1	POMT2	string_interaction
POMGNT1	SGCB	string_interaction
POMT1	POMT2	intact, string_interaction
POMT1	SGCA	string_interaction
POMT1	SGCB	string_interaction
POMT2	SGCB	string_interaction
SGCA	SGCB	string_interaction
SGCA	SGCD	string_interaction
SGCA	SGCG	string_interaction
SGCB	SGCD	biogrid_interaction, string_interaction
SGCB	SGCG	string_interaction
SGCD	SGCG	string_interaction

Structural data

PDB: 8 · AlphaFold-only: 9 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HMGCR	P04035	24
PLEC	Q15149	14
DYSF	O75923	11
POMGNT1	Q8WZA1	10
FKRP	Q9H9S5	8
CAPN3	P20807	5
ASTN2	O75129	3
TRIM32	Q13049	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TSPAN1	O60635	88.31
POMT1	Q9Y6A1	88.09
POMT2	Q9UKY4	87.96
TRAPPC11	Q7Z392	87.76
ANO5	Q75V66	82.22
SGCD	Q92629	81.43
SGCG	Q13326	80.24
SGCA	Q16586	80.15
SGCB	Q16585	76.67

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 34. Enrichment computed across 17 evidence-associated genes (15 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 15 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
DAG1 core M1 glycosylations	3	571.0×	2e-07	POMGNT1, POMT2, POMT1
DAG1 core M2 glycosylations	3	456.8×	3e-07	POMGNT1, POMT2, POMT1
Formation of the dystrophin-glycoprotein complex (DGC)	4	82.3×	1e-06	SGCA, SGCB, SGCD, SGCG
Non-integrin membrane-ECM interactions	4	41.1×	2e-05	SGCA, SGCB, SGCD, SGCG
Extracellular matrix organization	5	21.0×	2e-05	SGCA, SGCB, SGCD, SGCG, CAPN3
Defective POMT2 causes MDDGA2, MDDGB2 and MDDGC2	2	507.6×	2e-05	POMT2, POMT1
Defective POMT1 causes MDDGA1, MDDGB1 and MDDGC1	2	507.6×	2e-05	POMT2, POMT1
DAG1 core M3 glycosylations	2	253.8×	1e-04	POMT2, POMT1
Matriglycan biosynthesis on DAG1	2	108.8×	5e-04	FKRP, POMGNT1
Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	2	44.8×	0.003	POMT2, POMT1
Defective POMGNT1 causes MDDGA3, MDDGB3 and MDDGC3	1	380.7×	0.008	POMGNT1
Type I hemidesmosome assembly	1	69.2×	0.041	PLEC
Caspase-mediated cleavage of cytoskeletal proteins	1	63.4×	0.041	PLEC
Induction of Cell-Cell Fusion	1	58.6×	0.041	ANO5
Regulation of innate immune responses to cytosolic DNA	1	50.8×	0.042	TRIM32
Lanosterol biosynthesis	1	50.8×	0.042	HMGCR
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	24.6×	0.080	HMGCR
Late SARS-CoV-2 Infection Events	1	19.5×	0.095	ANO5
Smooth Muscle Contraction	1	17.7×	0.096	DYSF
Activation of gene expression by SREBF (SREBP)	1	17.3×	0.096	HMGCR
Regulation of clotting cascade	1	15.5×	0.101	ANO5
Assembly of collagen fibrils and other multimeric structures	1	13.4×	0.112	PLEC
Stimuli-sensing channels	1	9.1×	0.155	ANO5
RAB GEFs exchange GTP for GDP on RABs	1	8.3×	0.162	TRAPPC11
Degradation of the extracellular matrix	1	7.8×	0.163	CAPN3
Ion channel transport	1	6.4×	0.186	ANO5
PPARA activates gene expression	1	6.3×	0.186	HMGCR
SARS-CoV-2 Infection	1	5.4×	0.208	ANO5
SARS-CoV Infections	1	3.7×	0.280	ANO5
Antigen processing: Ubiquitination & Proteasome degradation	1	2.5×	0.380	TRIM32

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 17 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein O-linked glycosylation via mannose	4	220.3×	4e-07	FKRP, POMGNT1, POMT2, POMT1
muscle organ development	5	49.1×	4e-06	SGCA, SGCB, SGCD, SGCG, CAPN3
cardiac muscle cell development	3	110.1×	1e-04	SGCB, SGCD, PLEC
basement membrane organization	3	90.1×	2e-04	FKRP, POMGNT1, POMT2
localization of cell	2	330.4×	5e-04	FKRP, POMGNT1
reactive gliosis	2	283.2×	6e-04	POMGNT1, POMT2
gene expression	4	18.8×	0.001	SGCB, SGCG, POMGNT1, PLEC
cardiac muscle tissue development	2	104.3×	0.004	SGCD, SGCG
positive regulation of proteolysis	2	94.4×	0.004	CAPN3, TRIM32
heart contraction	2	90.1×	0.004	SGCD, SGCG
muscle cell cellular homeostasis	2	76.2×	0.005	CAPN3, TRIM32
dentate gyrus development	2	73.4×	0.005	POMGNT1, POMT2
monocyte activation involved in immune response	1	991.3×	0.008	DYSF
actin ubiquitination	1	991.3×	0.008	TRIM32
pentitol metabolic process	1	991.3×	0.008	FKRP
filtration diaphragm assembly	1	991.3×	0.008	FKRP
protein-containing complex organization	1	991.3×	0.008	PLEC
positive regulation of interleukin-17-mediated signaling pathway	1	991.3×	0.008	TRIM32
positive regulation of chemokine (C-C motif) ligand 20 production	1	991.3×	0.008	TRIM32
calcium-dependent self proteolysis	1	991.3×	0.008	CAPN3
actomyosin contractile ring assembly actin filament organization	1	991.3×	0.008	PLEC
sarcomere organization	2	45.1×	0.008	CAPN3, PLEC
positive regulation of satellite cell activation involved in skeletal muscle regeneration	1	495.6×	0.014	CAPN3
skeletal myofibril assembly	1	495.6×	0.014	PLEC
pentose metabolic process	1	495.6×	0.014	FKRP
coronary vasculature morphogenesis	1	495.6×	0.014	SGCD
protein O-linked glycosylation	2	26.4×	0.017	POMGNT1, POMT1
leukocyte migration involved in immune response	1	330.4×	0.018	PLEC
cellular response to hydrostatic pressure	1	330.4×	0.018	PLEC
muscle contraction	2	24.5×	0.018	SGCA, FKRP

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 16

Druggability breadth: 3 of 17 evidence-associated genes (18%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
HMGCR	SIMVASTATIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HMGCR	15	4
SGCA	0	0
SGCB	0	0
SGCD	0	0
SGCG	0	0
DYSF	0	0
CAPN3	0	0
TRIM32	0	0
ASTN2	0	0
FKRP	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SIMVASTATIN	4	HMGCR
PRAVASTATIN	4	HMGCR
PITAVASTATIN CALCIUM	4	HMGCR
CERIVASTATIN	4	HMGCR
ATORVASTATIN	4	HMGCR
ROSUVASTATIN	4	HMGCR
CISAPRIDE	4	HMGCR
FLUVASTATIN	4	HMGCR
LOVASTATIN	4	HMGCR
TANNIC ACID	4	HMGCR
PRAVASTATIN SODIUM	4	HMGCR
GLENVASTATIN	2	HMGCR
MEGLUTOL	2	HMGCR
MEVASTATIN	2	HMGCR
APOMINE	1	HMGCR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 5.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
HMGCR	153	Binding:148, Functional:5
PLEC	12	Binding:12
POMGNT1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HMGCR	1.1.1.34	hydroxymethylglutaryl-CoA reductase (NADPH)
CAPN3	3.4.22.54, 3.4.22.56	calpain-3, caspase-3
POMGNT1	2.4.1.312	protein O-mannose beta-1,4-N-acetylglucosaminyltransferase
POMT2	2.4.1.109	dolichyl-phosphate-mannose-protein mannosyltransferase
POMT1	2.4.1.109	dolichyl-phosphate-mannose-protein mannosyltransferase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
HMGCR	153

Pharmacogenomics

Cohort genes with a PharmGKB record: 17; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
HMGCR	1

Chemical tractability of cohort targets

15 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.

Compound	Max phase	Cohort target (bioactivity)
SIMVASTATIN	4	HMGCR
PRAVASTATIN	4	HMGCR
PITAVASTATIN CALCIUM	4	HMGCR
CERIVASTATIN	4	HMGCR
ATORVASTATIN	4	HMGCR
ROSUVASTATIN	4	HMGCR
CISAPRIDE	4	HMGCR
FLUVASTATIN	4	HMGCR
LOVASTATIN	4	HMGCR
TANNIC ACID	4	HMGCR
PRAVASTATIN SODIUM	4	HMGCR
GLENVASTATIN	2	HMGCR
MEGLUTOL	2	HMGCR
MEVASTATIN	2	HMGCR
APOMINE	1	HMGCR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	HMGCR
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	3	CAPN3, ASTN2, POMGNT1
D	Druggable family + AlphaFold only, no drug	2	POMT2, POMT1
E	Difficult family or no structure, no drug	11	SGCA, SGCB, SGCD, SGCG, DYSF, TRIM32, FKRP, TSPAN1, TRAPPC11, ANO5 (+1 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SGCA	0	—
SGCB	0	—
SGCD	0	—
SGCG	0	—
DYSF	0	—
CAPN3	0	—
TRIM32	0	—
ASTN2	0	—
FKRP	0	—
POMGNT1	1	—
POMT2	0	—
TSPAN1	0	—
TRAPPC11	0	—
ANO5	0	—
PLEC	12	—
POMT1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.