Muscle tissue disorder

Summary

Muscle tissue disorder (MONDO:0003939) is a disease (an umbrella term covering 13 Mondo subtypes) with 4 cohort genes (6 GWAS associations across 1 studies) and 20 clinical trials.

At a glance

• Umbrella term: 13 Mondo subtypes
• Cohort genes: 4
• GWAS associations: 6
• ClinVar variants: 5
• Clinical trials: 20

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	muscle tissue disorder
Mondo ID	MONDO:0003939
MeSH	D009135
DOID	DOID:0080000, DOID:66
ICD-10-CM	M60-M63
Anatomy (UBERON)	UBERON:0002385
Is cancer (heuristic)	no

Also known as: disease of muscle organ · disease of muscle tissue · disease or disorder of muscle organ · disease or disorder of muscle tissue · disorder of muscle organ · disorder of muscle tissue · muscle organ disease · muscle organ disease or disorder · muscle tissue disease · muscle tissue disease or disorder · muscular disorder

Data availability: 5 ClinVar variants · 6 GWAS associations (1 study).

Disease family

An umbrella term covering 13 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder

Related subtypes (21): autoimmune disorder of musculoskeletal system, musculoskeletal system benign neoplasm, musculoskeletal system cancer, Klippel-Feil syndrome, enthesopathy, fasciitis, skeletal system disorder, synovial chondromatosis, auriculoosteodysplasia, hypertrophic osteoarthropathy, primary, autosomal dominant, Upington disease, Ramon syndrome, osteoporosis-oculocutaneous hypopigmentation syndrome, short stature, Brussels type, wormian bone-multiple fractures-dentinogenesis imperfecta-skeletal dysplasia, CINCA syndrome, chondrodysplasia with joint dislocations, gPAPP type, ligament disorder, synovium disorder, disease of the tendon, Short stature, Dauber-Argente type

Subtypes (13): striated muscle rhabdoid tumor, septal myocardial infarction, tonsillar pillar cancer, atrophic muscular disease, cardiomyopathy, myalgic encephalomeyelitis/chronic fatigue syndrome, conduction system disorder, myostatin-related muscle hypertrophy, caveolinopathy, distal arthrogryposis, skeletal muscle disorder, myomatous neoplasm, Kocher-debre-Semelaigne syndrome

Genetics & variants

GWAS landscape

6 GWAS associations across 1 studies. Top hits map to 2 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs6667912	4e-08	TMEM9	G	1.33
rs76443348	3e-07	LINC01742 - HSPD1P19	T	2.55
rs17815112	4e-07	GALNT13-AS1 - RNA5SP107	A	0.77
rs35136807	4e-07	LINC02997 - RNU6-1232P	A	1.54
rs7564037	6e-07	RNU6-715P - RNA5SP106	G	0.57
rs11399393	7e-07	LINC02712	AC	1.3

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90131947	Murphy WA	2022	819	8,365	Pharmacogenomic Study of Statin-Associated Muscle Symptoms in the ODYSSEY OUTCOMES Trial.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	6

MAF distribution

Bucket	Variants
common (>=0.05)	5
low_freq (0.01-0.05)	1
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	3
intergenic_variant	3

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs6667912	1	201148730	C>G	0.34	intron_variant	TMEM9	4e-08	Tier 4: intronic/intergenic
rs76443348	20	58072670	C>A,T	0.01	intergenic_variant	LINC01742 - HSPD1P19	3e-07	Tier 4: intronic/intergenic
rs17815112	2	154457782	G>A	0.43	intergenic_variant	GALNT13-AS1 - RNA5SP107	4e-07	Tier 4: intronic/intergenic
rs35136807	5	68066792	AC>A	0.26	intergenic_variant	LINC02997 - RNU6-1232P	4e-07	Tier 4: intronic/intergenic
rs7564037	2	147667570	C>G	0.1	intron_variant	RNU6-715P - RNA5SP106	6e-07	Tier 4: intronic/intergenic
rs11399393	11	127318263	A>AC	0.45	intron_variant	LINC02712	7e-07	Tier 4: intronic/intergenic

ClinVar germline variants

5 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3338147	NM_213599.3(ANO5):c.648+4275A>C	ANO5	Uncertain significance	no assertion criteria provided
3338158	NM_213599.3(ANO5):c.649-1173A>G	ANO5	Uncertain significance	no assertion criteria provided
3338133	NM_000426.4(LAMA2):c.1783-22904T>A	LAMA2	Uncertain significance	no assertion criteria provided
3338128	NM_004369.4(COL6A3):c.3071-818G>A	COL6A3	Likely benign	no assertion criteria provided
3338143	NM_000540.3(RYR1):c.4161-526_4161-499del	RYR1	Likely benign	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 23 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RYR1	Orphanet:169186	Autosomal recessive centronuclear myopathy
RYR1	Orphanet:169189	Autosomal dominant centronuclear myopathy
RYR1	Orphanet:178145	Moderate multiminicore disease with hand involvement
RYR1	Orphanet:324581	Benign Samaritan congenital myopathy
RYR1	Orphanet:33108	Lethal multiple pterygium syndrome
RYR1	Orphanet:423	Malignant hyperthermia of anesthesia
RYR1	Orphanet:424107	Congenital myopathy with myasthenic-like onset
RYR1	Orphanet:466650	Exercise-induced malignant hyperthermia
RYR1	Orphanet:597	Central core disease
RYR1	Orphanet:700188	Calf-predominant weakness-gastrocnemius medialis atrophy-distal myopathy
RYR1	Orphanet:98905	Congenital multicore myopathy with external ophthalmoplegia
RYR1	Orphanet:99741	King-Denborough syndrome
COL6A3	Orphanet:464440	Primary dystonia, DYT27 type
COL6A3	Orphanet:610	Bethlem muscular dystrophy
COL6A3	Orphanet:646113	Intermediate collagen VI-related muscular dystrophy
COL6A3	Orphanet:75840	Ullrich congenital muscular dystrophy
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
LAMA2	Orphanet:258	Laminin subunit alpha 2-related congenital muscular dystrophy
LAMA2	Orphanet:565837	Laminin subunit alpha 2-related limb-girdle muscular dystrophy R23

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RYR1	HGNC:10483	ENSG00000196218	P21817	Ryanodine receptor 1	clinvar
COL6A3	HGNC:2213	ENSG00000163359	P12111	Collagen alpha-3(VI) chain	clinvar
ANO5	HGNC:27337	ENSG00000171714	Q75V66	Anoctamin-5	clinvar
LAMA2	HGNC:6482	ENSG00000196569	P24043	Laminin subunit alpha-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RYR1	Ryanodine receptor 1	Cytosolic calcium-activated calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytosol and thereby plays a key role in triggering muscle contraction following depolarization of T-tubules.
COL6A3	Collagen alpha-3(VI) chain	Collagen VI acts as a cell-binding protein.
ANO5	Anoctamin-5	Plays a role in plasma membrane repair in a process involving annexins.
LAMA2	Laminin subunit alpha-2	Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.5

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
Ion channel	1	27.9×	0.106
Antibody/Immunoglobulin	1	7.3×	0.195
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RYR1	Ion channel	yes		RIH_dom, B30.2/SPRY, Ryanodine_rcpt
COL6A3	Antibody/Immunoglobulin	yes		VWF_A, Kunitz_BPTI, FN3_dom
ANO5	Other/Unknown	no		Anoctamin, Anoct_dimer, Anoctamin_TM
LAMA2	Other/Unknown	no		Laminin_IV, EGF, Laminin_G

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	1
gluteal muscle	1
hindlimb stylopod muscle	1
skin of hip	1
stromal cell of endometrium	1
visceral pleura	1
cardiac muscle of right atrium	1
left ventricle myocardium	1
vastus lateralis	1
calcaneal tendon	1
mucosa of stomach	1
right ovary	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RYR1	214	broad	marker	gluteal muscle, gastrocnemius, hindlimb stylopod muscle
COL6A3	264	broad	marker	stromal cell of endometrium, visceral pleura, skin of hip
ANO5	220	broad	marker	cardiac muscle of right atrium, left ventricle myocardium, vastus lateralis
LAMA2	272	ubiquitous	marker	mucosa of stomach, calcaneal tendon, right ovary

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LAMA2	2,688
COL6A3	2,267
RYR1	2,177
ANO5	790

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COL6A3	P12111	6
RYR1	P21817	2
LAMA2	P24043	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ANO5	Q75V66	82.22

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 36. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
ECM proteoglycans	2	75.1×	0.006	COL6A3, LAMA2
Stimuli-sensing channels	2	68.0×	0.006	RYR1, ANO5
Ion channel transport	2	48.0×	0.008	RYR1, ANO5
Induction of Cell-Cell Fusion	1	219.6×	0.035	ANO5
MET promotes cell motility	1	150.3×	0.035	LAMA2
Attachment of bacteria to epithelial cells	1	124.1×	0.035	LAMA2
Laminin interactions	1	95.2×	0.035	LAMA2
MET activates PTK2 signaling	1	95.2×	0.035	LAMA2
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	92.1×	0.035	LAMA2
Signaling by MET	1	79.3×	0.035	LAMA2
Formation of the dystrophin-glycoprotein complex (DGC)	1	77.2×	0.035	LAMA2
Late SARS-CoV-2 Infection Events	1	73.2×	0.035	ANO5
Collagen chain trimerization	1	64.9×	0.035	COL6A3
Signaling by PDGF	1	63.4×	0.035	COL6A3
NCAM1 interactions	1	62.1×	0.035	COL6A3
Regulation of clotting cascade	1	58.3×	0.035	ANO5
Developmental Lineage of Pancreatic Ductal Cells	1	57.1×	0.035	LAMA2
Transport of small molecules	2	12.6×	0.035	RYR1, ANO5
Ion homeostasis	1	51.0×	0.036	RYR1
Assembly of collagen fibrils and other multimeric structures	1	50.1×	0.036	COL6A3
Collagen degradation	1	43.9×	0.038	COL6A3
Collagen biosynthesis and modifying enzymes	1	42.6×	0.038	COL6A3
Non-integrin membrane-ECM interactions	1	38.6×	0.040	LAMA2
Integrin cell surface interactions	1	33.6×	0.044	COL6A3
Cardiac conduction	1	27.2×	0.052	RYR1
SARS-CoV-2 Infection	1	20.1×	0.068	ANO5
Muscle contraction	1	19.3×	0.068	RYR1
Extracellular matrix organization	1	15.8×	0.080	LAMA2
SARS-CoV Infections	1	13.9×	0.087	ANO5
Signaling by Receptor Tyrosine Kinases	1	12.9×	0.090	LAMA2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
muscle organ development	2	83.4×	0.007	COL6A3, LAMA2
positive regulation of synaptic transmission, cholinergic	1	842.6×	0.011	LAMA2
regulation of basement membrane organization	1	702.2×	0.011	LAMA2
Schwann cell differentiation	1	601.9×	0.011	LAMA2
response to caffeine	1	601.9×	0.011	RYR1
release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1	421.3×	0.012	RYR1
cellular response to caffeine	1	383.0×	0.012	RYR1
ossification involved in bone maturation	1	351.1×	0.012	RYR1
positive regulation of integrin-mediated signaling pathway	1	324.1×	0.012	LAMA2
positive regulation of muscle cell differentiation	1	280.9×	0.012	LAMA2
cell adhesion	2	18.7×	0.013	COL6A3, LAMA2
striated muscle contraction	1	210.7×	0.013	RYR1
plasma membrane repair	1	145.3×	0.018	ANO5
skeletal muscle fiber development	1	135.9×	0.018	RYR1
maintenance of blood-brain barrier	1	120.4×	0.019	LAMA2
skin development	1	110.9×	0.019	RYR1
regulation of cytosolic calcium ion concentration	1	95.8×	0.020	RYR1
response to UV	1	91.6×	0.020	COL6A3
release of sequestered calcium ion into cytosol	1	86.0×	0.020	RYR1
regulation of embryonic development	1	82.6×	0.020	LAMA2
outflow tract morphogenesis	1	76.6×	0.021	RYR1
positive regulation of cell adhesion	1	68.0×	0.023	LAMA2
response to glucose	1	63.8×	0.023	COL6A3
protein homotetramerization	1	59.3×	0.023	RYR1
chloride transmembrane transport	1	59.3×	0.023	ANO5
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	52.7×	0.023	COL6A3
muscle contraction	1	52.0×	0.023	RYR1
monoatomic ion transmembrane transport	1	52.0×	0.023	ANO5
cellular response to calcium ion	1	50.1×	0.023	RYR1
neuron apoptotic process	1	46.3×	0.024	COL6A3

Therapeutics

Drugs indicated for this disease

0 approved, 4 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Alfacalcidol	Phase 3 (in late-stage trials)
Creatine	Phase 3 (in late-stage trials)
Etodolac	Phase 3 (in late-stage trials)
Lidocaine	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Ascorbic Acid, Ibuprofen, Levosimendan, Loxoprofen, Onabotulinumtoxina.

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RYR1	0	0
COL6A3	0	0
ANO5	0	0
LAMA2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
RYR1	16	Binding:13, Functional:3

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
RYR1	1

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	2	RYR1, COL6A3
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	ANO5, LAMA2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RYR1	16	—
COL6A3	0	—
ANO5	0	—
LAMA2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 20.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	20

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01166854	Not specified	RECRUITING	Characterization of Familial Myopathy and Paget Disease of Bone
NCT06721117	Not specified	NOT_YET_RECRUITING	Investigation of Grip Strength, Pain and Anxiety Levels in Dentists
NCT06809283	Not specified	RECRUITING	Observational Prospective PMCF Study to Confirm Performance and Safety of Intelect® Devices in Real World
NCT06870890	Not specified	NOT_YET_RECRUITING	Impact of Sarcopenia on Dyspnea in Patients With Asthma
NCT00540683	Not specified	WITHDRAWN	Measurement of the Distribution of Optical Properties in Adult Human Muscle
NCT03813485	Not specified	UNKNOWN	Electromyographic´s Differences Between Dry Needling in Tonic or Phasic Skeletal Muscle Fibers.
NCT03942445	Not specified	COMPLETED	In Vivo Analysis of Muscle Stem Cells in Chronic and Acute Lower Limb Ischemia (MyostemIschemia)
NCT04043832	Not specified	COMPLETED	A New Method of Muscle Strength Testing Using a Quantitative Ultrasonic Technique and a Convolutional Neural Network
NCT04625816	Not specified	COMPLETED	Comparison of Core Muscle Asymmetry Using Spine Balance 3D in Patients With Arthroscopic Shoulder Surgery
NCT04980586	Not specified	COMPLETED	Cheeks Appearance as a Novel Predictor of Obstructive Sleep Apnea The CASA Score Study
NCT05138926	Not specified	COMPLETED	Effect of Spinal Manipulation on Electromyography of the Masseter Muscle
NCT05173129	Not specified	COMPLETED	Posture Analysis for Patients With Haemophilia
NCT05261035	Not specified	COMPLETED	Stretching Exercises Versus Thermotherapy on Restless Legs Syndrome Symptoms
NCT05346705	Not specified	UNKNOWN	Effects of Newly-created Individualized Upper Airway Muscle Functional Training on Patients With OSA
NCT05732909	Not specified	COMPLETED	The Metabolic Effects of β-hydroxybutyrate on Working Skeletal Muscle
NCT05865418	Not specified	COMPLETED	A New Training to Enhance Physical Activity in Adolescents With Cerebral Palsy
NCT06138535	Not specified	COMPLETED	Evaluation of Digital Stabilizing Splint in Management of Masticatory Muscle Disorder
NCT06217211	Not specified	UNKNOWN	Eficacia Ventilatoria y Remolacha
NCT06305026	Not specified	COMPLETED	Protocol for a Diagnostic Test Accuracy of Histological Muscle and Skin Biopsies of Rheumatoid Arthritis Patients Revealing Objective Chronic Widespread Pain Phenomena Related to Fibromyalgia
NCT06677086	Not specified	COMPLETED	HIFEM for Musculoskeletal System Improvement