Skeletal muscle disorder

Summary

Skeletal muscle disorder (MONDO:0020120) is a disease (an umbrella term covering 13 Mondo subtypes) with 6 cohort genes and 2 clinical trials.

At a glance

• Umbrella term: 13 Mondo subtypes
• Cohort genes: 6
• ClinVar variants: 6
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	skeletal muscle disorder
Mondo ID	MONDO:0020120
Orphanet	98472
SNOMED CT	75047002
UMLS	C1533847
MedGen	735900
MedDRA	10028641
Anatomy (UBERON)	UBERON:0001134
Is cancer (heuristic)	no

Also known as: disease of skeletal muscle tissue · disease or disorder of skeletal muscle tissue · disorder of skeletal muscle tissue · skeletal muscle tissue disease · skeletal muscle tissue disease or disorder

Data availability: 6 ClinVar variants.

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 › skeletal muscle disorder

Related subtypes (12): 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, myomatous neoplasm, Kocher-debre-Semelaigne syndrome

Subtypes (13): anismus, skeletal muscle neoplasm, Volkmann contracture, myopathy, diaphragm disorder, anterior compartment of tibia syndrome, rotator cuff syndrome, Cyprus facial-neuromusculoskeletal syndrome, Tel Hashomer camptodactyly syndrome, muscular dystrophy-white matter spongiosis syndrome, acquired skeletal muscle disease, myotonic syndrome, hereditary skeletal muscle disorder

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

6 retrieved; paginated sample, class counts are floors:

3 conflicting classifications of pathogenicity, 1 pathogenic, 1 uncertain significance, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
986389	NM_004521.3(KIF5B):c.762CAA[1] (p.Asn255del)	KIF5B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4075385	NM_001031713.4(MCUR1):c.802C>T (p.Arg268Ter)	MCUR1	Pathogenic	criteria provided, single submitter
243086	NM_001349723.3(DNAJB5):c.43C>T (p.Pro15Ser)	DNAJB5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
222817	NM_004168.4(SDHA):c.830C>T (p.Thr277Met)	SDHA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
222856	NM_005726.6(TSFM):c.2T>G (p.Met1Arg)	TSFM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
949242	NM_000334.4(SCN4A):c.4805A>G (p.Asn1602Ser)	SCN4A	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 14 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SCN4A	Orphanet:681	Hypokalemic periodic paralysis
SCN4A	Orphanet:682	Hyperkalemic periodic paralysis
SCN4A	Orphanet:684	Paramyotonia congenita of Von Eulenburg
SCN4A	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
SCN4A	Orphanet:99734	Myotonia fluctuans
SCN4A	Orphanet:99735	Myotonia permanens
SCN4A	Orphanet:99736	Acetazolamide-responsive myotonia
SDHA	Orphanet:139411	Carney triad
SDHA	Orphanet:154	Familial isolated dilated cardiomyopathy
SDHA	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
SDHA	Orphanet:3208	Isolated succinate-CoQ reductase deficiency
SDHA	Orphanet:44890	Gastrointestinal stromal tumor
SDHA	Orphanet:97286	Carney-Stratakis syndrome
TSFM	Orphanet:168566	Fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCN4A	HGNC:10591	ENSG00000007314	P35499	Sodium channel protein type 4 subunit alpha	clinvar
SDHA	HGNC:10680	ENSG00000073578	P31040	Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial	clinvar
TSFM	HGNC:12367	ENSG00000123297	P43897	Elongation factor Ts, mitochondrial	clinvar
DNAJB5	HGNC:14887	ENSG00000137094	O75953	DnaJ homolog subfamily B member 5	clinvar
MCUR1	HGNC:21097	ENSG00000050393	Q96AQ8	Mitochondrial calcium uniporter regulator 1	clinvar
KIF5B	HGNC:6324	ENSG00000170759	P33176	Kinesin-1 heavy chain	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCN4A	Sodium channel protein type 4 subunit alpha	Pore-forming subunit of Nav1.4, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
SDHA	Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial	Flavoprotein (FP) subunit of succinate dehydrogenase (SDH) that is involved in complex II of the mitochondrial electron transport chain and is responsible for transferring electrons from succinate to ubiquinone (coenzyme Q).
TSFM	Elongation factor Ts, mitochondrial	Associates with the EF-Tu.GDP complex and induces the exchange of GDP to GTP.
MCUR1	Mitochondrial calcium uniporter regulator 1	Key regulator of mitochondrial calcium uniporter (MCU) required for calcium entry into mitochondrion.
KIF5B	Kinesin-1 heavy chain	Microtubule-dependent motor required for normal distribution of mitochondria and lysosomes.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.33

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	18.6×	0.158
Enzyme (other)	1	2.0×	0.458
Other/Unknown	4	1.2×	0.458

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCN4A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a4su_mammal
SDHA	Other/Unknown	no		FRD_SDH_FAD_BS, FAD-dep_OxRdtase_2_FAD-bd, Succ_DH_flav_su_fwd
TSFM	Other/Unknown	no		Transl_elong_EFTs/EF1B, UBA-like_sf, Transl_elong_EFTs/EF1B_dimer
DNAJB5	Other/Unknown	no		DnaJ_domain, DnaJ_C, HSP40/DnaJ_pept-bd
MCUR1	Other/Unknown	no		CCDC90-like
KIF5B	Enzyme (other)	yes	5.6.1.3	Kinesin_motor_dom, Kinesin_motor_CS, P-loop_NTPase

Expression context

Cohort genes with no expression data: 0.

5 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	2
hindlimb stylopod muscle	2
skeletal muscle tissue of rectus abdominis	1
apex of heart	1
heart left ventricle	1
mucosa of transverse colon	1
left adrenal gland	1
right adrenal gland	1
right adrenal gland cortex	1
saphenous vein	1
amniotic fluid	1
decidua	1
jejunal mucosa	1
caput epididymis	1
cauda epididymis	1
cranial nerve II	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCN4A	153	tissue_specific	yes	hindlimb stylopod muscle, gastrocnemius, skeletal muscle tissue of rectus abdominis
SDHA	143	ubiquitous	marker	apex of heart, heart left ventricle, mucosa of transverse colon
TSFM	134	ubiquitous	marker	right adrenal gland, left adrenal gland, right adrenal gland cortex
DNAJB5	241	ubiquitous	marker	hindlimb stylopod muscle, saphenous vein, gastrocnemius
MCUR1	288	ubiquitous	marker	jejunal mucosa, decidua, amniotic fluid
KIF5B	303	ubiquitous	marker	cauda epididymis, caput epididymis, cranial nerve II

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SDHA	6,141
KIF5B	3,606
TSFM	3,286
DNAJB5	2,590
SCN4A	1,704
MCUR1	932

Structural data

PDB: 4 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KIF5B	P33176	31
SDHA	P31040	5
SCN4A	P35499	3
TSFM	P43897	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DNAJB5	O75953	80.69
MCUR1	Q96AQ8	70.82

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 37. Enrichment computed across 6 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
RHO GTPases activate KTN1	1	259.6×	0.068	KIF5B
Maturation of TCA enzymes and regulation of TCA cycle	1	142.8×	0.068	SDHA
Insulin processing	1	114.2×	0.068	KIF5B
Citric acid cycle (TCA cycle)	1	105.7×	0.068	SDHA
Interaction between L1 and Ankyrins	1	92.1×	0.068	SCN4A
Phase 0 - rapid depolarisation	1	86.5×	0.068	SCN4A
Peptide hormone metabolism	1	68.0×	0.068	KIF5B
Signaling by ALK in cancer	1	68.0×	0.068	KIF5B
Kinesins	1	44.6×	0.087	KIF5B
Signaling by ALK fusions and activated point mutants	1	37.6×	0.087	KIF5B
Golgi-to-ER retrograde transport	1	33.2×	0.087	KIF5B
Mitochondrial translation elongation	1	31.7×	0.087	TSFM
L1CAM interactions	1	30.1×	0.087	SCN4A
COPI-dependent Golgi-to-ER retrograde traffic	1	27.7×	0.087	KIF5B
Cardiac conduction	1	27.2×	0.087	SCN4A
Intra-Golgi and retrograde Golgi-to-ER traffic	1	26.2×	0.087	KIF5B
Respiratory electron transport	1	23.8×	0.087	SDHA
MHC class II antigen presentation	1	22.3×	0.087	KIF5B
Aerobic respiration and respiratory electron transport	1	22.1×	0.087	SDHA
Muscle contraction	1	19.3×	0.094	SCN4A
RHO GTPase Effectors	1	17.0×	0.099	KIF5B
Factors involved in megakaryocyte development and platelet production	1	16.6×	0.099	KIF5B
Diseases of signal transduction by growth factor receptors and second messengers	1	14.2×	0.110	KIF5B
Axon guidance	1	11.3×	0.132	SCN4A
Nervous system development	1	10.7×	0.133	SCN4A
Membrane Trafficking	1	9.3×	0.141	KIF5B
Hemostasis	1	9.0×	0.141	KIF5B
Vesicle-mediated transport	1	8.7×	0.141	KIF5B
Signaling by Rho GTPases	1	8.6×	0.141	KIF5B
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	8.4×	0.141	KIF5B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of skeletal muscle contraction by action potential	1	2808.7×	0.009	SCN4A
regulation of modification of synapse structure, modulating synaptic transmission	1	1404.3×	0.009	KIF5B
mitochondrial translational elongation	1	702.2×	0.009	TSFM
anterograde neuronal dense core vesicle transport	1	702.2×	0.009	KIF5B
succinate metabolic process	1	561.7×	0.009	SDHA
mitochondrial electron transport, succinate to ubiquinone	1	561.7×	0.009	SDHA
retrograde neuronal dense core vesicle transport	1	561.7×	0.009	KIF5B
cytoplasm organization	1	468.1×	0.009	KIF5B
plus-end-directed vesicle transport along microtubule	1	468.1×	0.009	KIF5B
mitocytosis	1	468.1×	0.009	KIF5B
stress granule disassembly	1	401.2×	0.009	KIF5B
anterograde dendritic transport of neurotransmitter receptor complex	1	401.2×	0.009	KIF5B
positive regulation of potassium ion transport	1	351.1×	0.009	KIF5B
anterograde axonal protein transport	1	351.1×	0.009	KIF5B
positive regulation of mitochondrial calcium ion concentration	1	280.9×	0.011	MCUR1
mitochondrion transport along microtubule	1	234.1×	0.012	KIF5B
calcium import into the mitochondrion	1	200.6×	0.013	MCUR1
protein heterooligomerization	1	175.5×	0.014	MCUR1
mitochondrial calcium ion transmembrane transport	1	165.2×	0.014	MCUR1
positive regulation of synaptic transmission, GABAergic	1	165.2×	0.014	KIF5B
vesicle transport along microtubule	1	147.8×	0.014	KIF5B
centrosome localization	1	147.8×	0.014	KIF5B
respiratory electron transport chain	1	140.4×	0.014	SDHA
synaptic vesicle transport	1	140.4×	0.014	KIF5B
calcium ion import	1	133.8×	0.014	MCUR1
cardiac muscle cell action potential involved in contraction	1	117.0×	0.015	SCN4A
lysosome localization	1	87.8×	0.019	KIF5B
tricarboxylic acid cycle	1	85.1×	0.019	SDHA
natural killer cell mediated cytotoxicity	1	72.0×	0.022	KIF5B
generation of precursor metabolites and energy	1	57.3×	0.027	MCUR1

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 6 evidence-associated genes (50%) 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
SCN4A	CARBAMAZEPINE
SDHA	LINEZOLID
KIF5B	LENVATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN4A	24	4
KIF5B	3	4
SDHA	1	4
TSFM	0	0
DNAJB5	0	0
MCUR1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CARBAMAZEPINE	4	SCN4A
PHENYTOIN	4	SCN4A
LAMOTRIGINE	4	SCN4A
RILUZOLE	4	SCN4A
LIDOCAINE	4	SCN4A
IMIPRAMINE	4	SCN4A
SERTINDOLE	4	SCN4A
PIMOZIDE	4	SCN4A
NIFEDIPINE	4	SCN4A
DILTIAZEM	4	SCN4A
MIBEFRADIL	4	SCN4A
HALOPERIDOL	4	SCN4A
MEXILETINE	4	SCN4A
AMITRIPTYLINE	4	SCN4A
AMIODARONE	4	SCN4A
CHLORPROMAZINE	4	SCN4A
LINEZOLID	4	SDHA
LENVATINIB	4	KIF5B
CABOZANTINIB	4	KIF5B
VANDETANIB	4	KIF5B
VIXOTRIGINE	3	SCN4A
ELECLAZINE	3	SCN4A
TETRODOTOXIN	3	SCN4A
TEDISAMIL	3	SCN4A
NITRENDIPINE	3	SCN4A
AJMALINE	3	SCN4A
PF-05089771	2	SCN4A
CIFENLINE	2	SCN4A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
SCN4A	95	Binding:69, Functional:18, ADMET:7, Toxicity:1
KIF5B	43	Binding:37, Functional:6
SDHA	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KIF5B	5.6.1.3	plus-end-directed kinesin ATPase

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

28 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)
CARBAMAZEPINE	4	SCN4A
PHENYTOIN	4	SCN4A
LAMOTRIGINE	4	SCN4A
RILUZOLE	4	SCN4A
LIDOCAINE	4	SCN4A
IMIPRAMINE	4	SCN4A
SERTINDOLE	4	SCN4A
PIMOZIDE	4	SCN4A
NIFEDIPINE	4	SCN4A
DILTIAZEM	4	SCN4A
MIBEFRADIL	4	SCN4A
HALOPERIDOL	4	SCN4A
MEXILETINE	4	SCN4A
AMITRIPTYLINE	4	SCN4A
AMIODARONE	4	SCN4A
CHLORPROMAZINE	4	SCN4A
LINEZOLID	4	SDHA
LENVATINIB	4	KIF5B
CABOZANTINIB	4	KIF5B
VANDETANIB	4	KIF5B
VIXOTRIGINE	3	SCN4A
ELECLAZINE	3	SCN4A
TETRODOTOXIN	3	SCN4A
TEDISAMIL	3	SCN4A
NITRENDIPINE	3	SCN4A
AJMALINE	3	SCN4A
PF-05089771	2	SCN4A
CIFENLINE	2	SCN4A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	SCN4A, SDHA, KIF5B
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	TSFM, DNAJB5, MCUR1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TSFM	0	—
DNAJB5	0	—
MCUR1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04262258	Not specified	COMPLETED	Effects of a Blueberry Enriched Diet on the Skeletal Muscle Regenerative Process
NCT05779202	Not specified	COMPLETED	Observational Study on Cardiac Biomarkers Testing in Patients with Muscular Dystrophy Cardiomyopathy