Congenital myopathy

Summary

Congenital myopathy (MONDO:0019952) is a disease (an umbrella term covering 54 Mondo subtypes) caused by variants in CACNA1S, FXR1, HACD1, and 2 other genes, with 44 cohort genes and 13 clinical trials. The dominant Reactome pathway is Striated Muscle Contraction (5 cohort genes).

At a glance

• Prevalence: 1-9 / 100 000 (United States) [Orphanet-validated]
• Causal genes: CACNA1S (GenCC Strong), FXR1 (GenCC Strong), HACD1 (GenCC Strong), SCN4A (GenCC Strong) (+1 more)
• Umbrella term: 54 Mondo subtypes
• Cohort genes: 44
• ClinVar variants: 81
• Clinical trials: 13

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	3.8	United States	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital myopathy
Mondo ID	MONDO:0019952
OMIM	117000
Orphanet	97245
DOID	DOID:0080100, DOID:0081337
ICD-11	1185572073
UMLS	C0270960
MedGen	124381
GARD	0005898
MedDRA	10062547
Is cancer (heuristic)	no

Also known as: Batten Turner congenital myopathy · congenital myopathy · myopathy congenital

Data availability: 81 ClinVar variants · 14 GenCC gene-disease records.

Disease family

An umbrella term covering 54 Mondo subtypes.

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

Related subtypes (31): polyglucosan body myopathy, muscular atrophy, myopathy of extraocular muscle, acute quadriplegic myopathy, myofascial pain syndrome, myopathy with abnormal lipid metabolism, proximal myopathy with focal depletion of mitochondria, Brody myopathy, rippling muscle disease, myopathy due to myoadenylate deaminase deficiency, proximal myopathy with extrapyramidal signs, intermediate nemaline myopathy, hereditary inclusion-body myopathy, hereditary continuous muscle fiber activity, muscular dystrophy, metabolic myopathy, myositis disease, collagen 6-related myopathy, myopathy caused by variation in CRPPA, drug-induced myopathy, myopathy caused by variation in FKRP, myopathy caused by variation in FKTN, myopathy caused by variation in POMGNT1, myopathy caused by variation in POMGNT2, myopathy caused by variation in POMT1, myopathy caused by variation in POMT2, myopathy caused by variation in GMPPB, FHL1-related myopathy, myopathy, sarcoplasmic body, myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis 2, myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis

Subtypes (54): Ullrich congenital muscular dystrophy, congenital structural myopathy, Bethlem myopathy, MYH7-related skeletal myopathy, tubular aggregate myopathy, cylindrical spirals myopathy, congenital myopathy 7A, myosin storage, autosomal dominant, intellectual disability-myopathy-short stature-endocrine defect syndrome, myopathy, myosin storage, autosomal recessive, Bailey-Bloch congenital myopathy, fingerprint body myopathy, myopathy, proximal, and ophthalmoplegia, Compton-North congenital myopathy, MEGF10-related myopathy, fetal akinesia-cerebral and retinal hemorrhage syndrome, Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome, severe hypotonia-psychomotor developmental delay-strabismus-cardiac septal defect syndrome, myopathy with hexagonally cross-linked tubular arrays, benign Samaritan congenital myopathy, congenital generalized hypercontractile muscle stiffness syndrome, hyaline body myopathy, centronuclear myopathy, reducing body myopathy, myopathy, congenital, with tremor, myopathy, congenital, progressive, with scoliosis, myopathy, congenital, with structured cores and z-line abnormalities, myopathy, congenital, with respiratory insufficiency and bone fractures, myopathy, congenital proximal, with minicore lesions, myopathy, congenital, with diaphragmatic defects, respiratory insufficiency, and dysmorphic facies, congenital myopathy with reduced type 2 muscle fibers, alpha-actinopathy, SELENON-related myopathy, TPM3-related myopathy, SCN4A-related myopathy, autosomal recessive, RYR1-related myopathy, TTN-related myopathy, TPM2-related myopathy, Batten-Turner congenital myopathy, TOR1AIP1-related myopathy, congenital myopathy 11, congenital myopathy 15, congenital myopathy 18, congenital myopathy 10b, mild variant, congenital myopathy 2b, severe infantile, autosomal recessive, congenital myopathy 2c, severe infantile, autosomal dominant, congenital myopathy 20, congenital myopathy 21 with early respiratory failure, congenital myopathy 22A, classic, congenital myopathy 22B, severe fetal, congenital myopathy 25, congenital myopathy 26, congenital myopathy 27, congenital myopathy 28 with rigid spine, congenital myopathy 29 with contractures

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

81 retrieved; paginated sample, class counts are floors:

25 uncertain significance, 20 conflicting classifications of pathogenicity, 9 likely pathogenic, 9 pathogenic, 7 pathogenic/likely pathogenic, 5 likely benign, 3 benign/likely benign, 2 benign, 1 uncertain significance; drug response

ClinVar	Variant (HGVS)	Gene	Classification	Review
42106	NM_001100.4(ACTA1):c.143G>A (p.Gly48Asp)	ACTA1	Pathogenic	criteria provided, multiple submitters, no conflicts
654469	NM_001100.4(ACTA1):c.283G>A (p.Glu95Lys)	ACTA1	Pathogenic	reviewed by expert panel
3376615	NM_000069.3(CACNA1S):c.1084del (p.Asp362fs)	CACNA1S	Pathogenic	criteria provided, single submitter
3376719	NM_000069.3(CACNA1S):c.4516_4517del (p.Leu1506fs)	CACNA1S	Pathogenic	criteria provided, single submitter
18379	NM_000079.4(CHRNA1):c.517G>A (p.Gly173Ser)	CHRNA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4072104	NM_004369.4(COL6A3):c.6816G>A (p.Lys2272=)	COL6A3	Pathogenic	criteria provided, single submitter
31691	NM_016042.4(EXOSC3):c.92G>C (p.Gly31Ala)	EXOSC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
645345	NM_000334.4(SCN4A):c.2919del (p.Glu974fs)	GH-LCR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3024350	NM_020647.4(JPH1):c.1510del (p.Glu504fs)	JPH1	Pathogenic	criteria provided, single submitter
421289	NM_015443.4(KANSL1):c.868C>T (p.Arg290Ter)	KANSL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
694311	NM_000257.4(MYH7):c.5655+5G>C	MYH7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1954527	NM_001164508.2(NEB):c.12162G>A (p.Trp4054Ter)	NEB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
420125	NM_001164508.2(NEB):c.2415+1G>A	NEB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3341103	NM_014370.4(SRPK3):c.203_204del (p.Pro68fs)	SRPK3	Pathogenic	criteria provided, single submitter
3341104	NM_001267550.2(TTN):c.42521G>A (p.Trp14174Ter)	TTN	Pathogenic	criteria provided, single submitter
2865368	NM_015346.4(ZFYVE26):c.1093del (p.Leu365fs)	ZFYVE26	Pathogenic	criteria provided, multiple submitters, no conflicts
424835	NM_001267550.2(TTN):c.[102956_102958delCAA];[62722C>T]		Likely pathogenic	criteria provided, single submitter
2582795	NM_001100.4(ACTA1):c.766C>G (p.Arg256Gly)	ACTA1	Likely pathogenic	criteria provided, single submitter
2582805	NM_001100.4(ACTA1):c.925C>T (p.Pro309Ser)	ACTA1	Likely pathogenic	criteria provided, single submitter
2582826	NM_001100.4(ACTA1):c.772C>G (p.Arg258Gly)	ACTA1	Likely pathogenic	criteria provided, single submitter
2683802	NM_020647.4(JPH1):c.373del (p.Asp125fs)	JPH1	Likely pathogenic	criteria provided, single submitter
2683803	NM_020647.4(JPH1):c.354C>A (p.Tyr118Ter)	JPH1	Likely pathogenic	criteria provided, single submitter
2683804	NM_020647.4(JPH1):c.1738del (p.Leu580fs)	JPH1	Likely pathogenic	criteria provided, single submitter
1515967	NM_032578.4(MYPN):c.1317+1G>A	MYPN	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3075953	NM_145064.3(STAC3):c.88_91del (p.Leu30fs)	STAC3	Likely pathogenic	criteria provided, single submitter
12975	NM_000540.3(RYR1):c.14693T>C (p.Ile4898Thr)	RYR1	Uncertain significance; drug response	reviewed by expert panel
389968	NM_144988.4(ALG14):c.220G>A (p.Asp74Asn)	ALG14-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2439137	NM_007347.5(AP4E1):c.275A>G (p.Tyr92Cys)	AP4E1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2664823	NM_006828.4(ASCC3):c.2554C>T (p.Arg852Ter)	ASCC3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
212860	NM_000071.3(CBS):c.1105C>T (p.Arg369Cys)	CBS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 114 · Orphanet: 117 · 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
GNE	Definitive	Autosomal recessive	GNE myopathy	13
HACD1	Definitive	Autosomal recessive	congenital myopathy 11	3
SCN4A	Definitive	Autosomal recessive	SCN4A-related myopathy, autosomal recessive	24
TTN	Definitive	Autosomal recessive	early-onset myopathy with fatal cardiomyopathy	21
CACNA1S	Strong	Autosomal dominant	congenital myopathy	11
DNAJB4	Strong	Autosomal recessive	congenital myopathy 21 with early respiratory failure	6
FXR1	Strong	Autosomal recessive	myopathy, congenital, with respiratory insufficiency and bone fractures	4
TNNT3	Strong	Autosomal recessive	congenital myopathy	7
TPM2	Strong	Autosomal dominant	congenital myopathy 23	12
TUBA4A	Moderate	Autosomal dominant	congenital myopathy	8
COL6A6	Limited	Autosomal recessive	myopathy	2
RYR3	Limited	Autosomal recessive	congenital myopathy	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TNNT3	Orphanet:1146	Distal arthrogryposis type 1
TNNT3	Orphanet:1147	Sheldon-Hall syndrome
TTN	Orphanet:140922	Titin-related limb-girdle muscular dystrophy R10
TTN	Orphanet:154	Familial isolated dilated cardiomyopathy
TTN	Orphanet:169186	Autosomal recessive centronuclear myopathy
TTN	Orphanet:178464	Hereditary myopathy with early respiratory failure
TTN	Orphanet:289377	Early-onset myopathy with fatal cardiomyopathy
TTN	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
TTN	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
TTN	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
TTN	Orphanet:324604	Classic multiminicore myopathy
TTN	Orphanet:334	Hereditary atrial fibrillation
TTN	Orphanet:466921	Childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome
TTN	Orphanet:609	Tibial muscular dystrophy
TTN	Orphanet:707983	Early-onset autosomal recessive TTN-related distal myopathy
CACNA1S	Orphanet:397755	Periodic paralysis with transient compartment-like syndrome
CACNA1S	Orphanet:423	Malignant hyperthermia of anesthesia
CACNA1S	Orphanet:681	Hypokalemic periodic paralysis
CACNA1S	Orphanet:79102	Thyrotoxic periodic paralysis
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
TPM2	Orphanet:1146	Distal arthrogryposis type 1
TPM2	Orphanet:1147	Sheldon-Hall syndrome
TPM2	Orphanet:171436	Typical nemaline myopathy
TPM2	Orphanet:171439	Childhood-onset nemaline myopathy
TPM2	Orphanet:171881	Cap myopathy
TPM2	Orphanet:2020	Congenital fiber-type disproportion myopathy
DNAJB4	Orphanet:700170	DNAJB4-related distal myopathy
GNE	Orphanet:3166	Sialuria
GNE	Orphanet:438207	Severe autosomal recessive macrothrombocytopenia
GNE	Orphanet:602	GNE myopathy
HACD1	Orphanet:2020	Congenital fiber-type disproportion myopathy
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
SYT2	Orphanet:98914	Presynaptic congenital myasthenic syndromes

Cohort genes → proteins

44 cohort genes, 40 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	44

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TNNT3	HGNC:11950	ENSG00000130595	P45378	Troponin T, fast skeletal muscle	gencc,clinvar
TTN	HGNC:12403	ENSG00000155657	Q8WZ42	Titin	gencc,clinvar
CACNA1S	HGNC:1397	ENSG00000081248	Q13698	Voltage-dependent L-type calcium channel subunit alpha-1S	gencc,clinvar
COL6A6	HGNC:27023	ENSG00000206384	A6NMZ7	Collagen alpha-6(VI) chain	gencc,clinvar
FXR1	HGNC:4023	ENSG00000114416	P51114	RNA-binding protein FXR1	gencc,clinvar
RYR3	HGNC:10485	ENSG00000198838	Q15413	Ryanodine receptor 3	gencc
SCN4A	HGNC:10591	ENSG00000007314	P35499	Sodium channel protein type 4 subunit alpha	gencc
TPM2	HGNC:12011	ENSG00000198467	P07951	Tropomyosin beta chain	gencc
TUBA4A	HGNC:12407	ENSG00000127824	P68366	Tubulin alpha-4A chain	gencc
DNAJB4	HGNC:14886	ENSG00000162616	Q9UDY4	DnaJ homolog subfamily B member 4	gencc
GNE	HGNC:23657	ENSG00000159921	Q9Y223	Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase	gencc
HACD1	HGNC:9639	ENSG00000165996	B0YJ81	Very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase 1	gencc
RYR1	HGNC:10483	ENSG00000196218	P21817	Ryanodine receptor 1	clinvar
SRPK3	HGNC:11402	ENSG00000184343	Q9UPE1	SRSF protein kinase 3	clinvar
SYT2	HGNC:11510	ENSG00000143858	Q8N9I0	Synaptotagmin-2	clinvar
USP9X	HGNC:12632	ENSG00000124486	Q93008	Ubiquitin carboxyl-terminal hydrolase 9X	clinvar
ACTA1	HGNC:129	ENSG00000143632	P68133	Actin, alpha skeletal muscle	clinvar
MYO15B	HGNC:14083	ENSG00000266714	Q96JP2	Unconventional myosin-XVB	clinvar
JPH1	HGNC:14201	ENSG00000104369	Q9HDC5	Junctophilin-1	clinvar
CBS	HGNC:1550	ENSG00000160200	P35520	Cystathionine beta-synthase	clinvar
SPEG	HGNC:16901	ENSG00000072195	Q15772	Striated muscle preferentially expressed protein kinase	clinvar
EXOSC3	HGNC:17944	ENSG00000107371	Q9NQT5	Exosome complex component RRP40	clinvar
TRPV4	HGNC:18083	ENSG00000111199	Q9HBA0	Transient receptor potential cation channel subfamily V member 4	clinvar
ASCC3	HGNC:18697	ENSG00000112249	Q8N3C0	Activating signal cointegrator 1 complex subunit 3	clinvar
CHRNA1	HGNC:1955	ENSG00000138435	P02708	Acetylcholine receptor subunit alpha	clinvar
ZFYVE26	HGNC:20761	ENSG00000072121	Q68DK2	Zinc finger FYVE domain-containing protein 26	clinvar
COL6A2	HGNC:2212	ENSG00000142173	P12110	Collagen alpha-2(VI) chain	clinvar
COL6A3	HGNC:2213	ENSG00000163359	P12111	Collagen alpha-3(VI) chain	clinvar
MYPN	HGNC:23246	ENSG00000138347	Q86TC9	Myopalladin	clinvar
KANSL1	HGNC:24565	ENSG00000120071	Q7Z3B3	KAT8 regulatory NSL complex subunit 1	clinvar
STAC3	HGNC:28423	ENSG00000185482	Q96MF2	SH3 and cysteine-rich domain-containing protein 3	clinvar
DNA2	HGNC:2939	ENSG00000138346	P51530	DNA replication ATP-dependent helicase/nuclease DNA2	clinvar
ALG13	HGNC:30881	ENSG00000101901	Q9NP73	UDP-N-acetylglucosamine transferase subunit ALG13	clinvar
INPP5K	HGNC:33882	ENSG00000132376	Q9BT40	Inositol polyphosphate 5-phosphatase K	clinvar
SNHG14	HGNC:37462	ENSG00000224078		small nucleolar RNA host gene 14	clinvar
ADGRG1	HGNC:4512	ENSG00000205336	Q9Y653	Adhesion G-protein coupled receptor G1	clinvar
MHRT	HGNC:51291			myosin heavy chain associated RNA transcript	clinvar
TCF4-AS1	HGNC:51642	ENSG00000267028		TCF4 antisense RNA 1	clinvar
CNN3-DT	HGNC:54176	ENSG00000235501		CNN3 divergent transcript	clinvar
AP4E1	HGNC:573	ENSG00000081014	Q9UPM8	AP-4 complex subunit epsilon-1	clinvar
MTRR	HGNC:7473	ENSG00000124275	Q9UBK8	Methionine synthase reductase	clinvar
MYH7	HGNC:7577	ENSG00000092054	P12883	Myosin-7	clinvar
NEB	HGNC:7720	ENSG00000183091	P20929	Nebulin	clinvar
OCRL	HGNC:8108	ENSG00000122126	Q01968	Inositol polyphosphate 5-phosphatase OCRL	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TNNT3	Troponin T, fast skeletal muscle	Troponin T is the tropomyosin-binding subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.
TTN	Titin	Key component in the assembly and functioning of vertebrate striated muscles.
CACNA1S	Voltage-dependent L-type calcium channel subunit alpha-1S	Pore-forming, alpha-1S subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents in skeletal muscle.
COL6A6	Collagen alpha-6(VI) chain	Collagen VI acts as a cell-binding protein.
FXR1	RNA-binding protein FXR1	mRNA-binding protein that acts as a regulator of mRNAs translation and/or stability, and which is required for various processes, such as neurogenesis, muscle development and spermatogenesis.
RYR3	Ryanodine receptor 3	Cytosolic calcium-activated calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytoplasm in muscle and thereby plays a role in triggering muscle contraction.
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.
TPM2	Tropomyosin beta chain	Binds to actin filaments in muscle and non-muscle cells.
TUBA4A	Tubulin alpha-4A chain	Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers.
DNAJB4	DnaJ homolog subfamily B member 4	Probable chaperone.
GNE	Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase	Bifunctional enzyme that possesses both UDP-N-acetylglucosamine 2-epimerase and N-acetylmannosamine kinase activities, and serves as the initiator of the biosynthetic pathway leading to the production of N-acetylneuraminic acid (NeuAc), a…
HACD1	Very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase 1	Catalyzes the third of the four reactions of the long-chain fatty acids elongation cycle.
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.
SRPK3	SRSF protein kinase 3	Serine/arginine-rich protein-specific kinase which specifically phosphorylates its substrates at serine residues located in regions rich in arginine/serine dipeptides, known as RS domains.
SYT2	Synaptotagmin-2	Exhibits calcium-dependent phospholipid and inositol polyphosphate binding properties.
USP9X	Ubiquitin carboxyl-terminal hydrolase 9X	Deubiquitinase involved both in the processing of ubiquitin precursors and of ubiquitinated proteins.
ACTA1	Actin, alpha skeletal muscle	Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells.
JPH1	Junctophilin-1	Junctophilins contribute to the formation of junctional membrane complexes (JMCs) which link the plasma membrane with the endoplasmic or sarcoplasmic reticulum in excitable cells.
CBS	Cystathionine beta-synthase	Hydro-lyase catalyzing the first step of the transsulfuration pathway, where the hydroxyl group of L-serine is displaced by L-homocysteine in a beta-replacement reaction to form L-cystathionine, the precursor of L-cysteine.
SPEG	Striated muscle preferentially expressed protein kinase	Isoform 3 may have a role in regulating the growth and differentiation of arterial smooth muscle cells.
EXOSC3	Exosome complex component RRP40	Non-catalytic component of the RNA exosome complex which has 3’->5’ exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events.
TRPV4	Transient receptor potential cation channel subfamily V member 4	Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity.
ASCC3	Activating signal cointegrator 1 complex subunit 3	ATPase involved both in DNA repair and rescue of stalled ribosomes. 3’-5’ DNA helicase involved in repair of alkylated DNA: promotes DNA unwinding to generate single-stranded substrate needed for ALKBH3, enabling ALKBH3 to process alkylate…
CHRNA1	Acetylcholine receptor subunit alpha	Upon acetylcholine binding, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane.
ZFYVE26	Zinc finger FYVE domain-containing protein 26	Phosphatidylinositol 3-phosphate-binding protein required for the abscission step in cytokinesis: recruited to the midbody during cytokinesis and acts as a regulator of abscission.
COL6A2	Collagen alpha-2(VI) chain	Collagen VI acts as a cell-binding protein.
COL6A3	Collagen alpha-3(VI) chain	Collagen VI acts as a cell-binding protein.
MYPN	Myopalladin	Component of the sarcomere that tethers together nebulin (skeletal muscle) and nebulette (cardiac muscle) to alpha-actinin, at the Z lines.
KANSL1	KAT8 regulatory NSL complex subunit 1	Non-catalytic component of the NSL histone acetyltransferase complex, a multiprotein complex that mediates histone H4 acetylation at ‘Lys-5’- and ‘Lys-8’ (H4K5ac and H4K8ac) at transcription start sites and promotes transcription initiatio…
STAC3	SH3 and cysteine-rich domain-containing protein 3	Required for normal excitation-contraction coupling in skeletal muscle and for normal muscle contraction in response to membrane depolarization.
DNA2	DNA replication ATP-dependent helicase/nuclease DNA2	Key enzyme involved in DNA replication and DNA repair in nucleus and mitochondrion.
ALG13	UDP-N-acetylglucosamine transferase subunit ALG13	Catalytic subunit of the UDP-N-acetylglucosamine transferase complex that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation.
INPP5K	Inositol polyphosphate 5-phosphatase K	Inositol 5-phosphatase which acts on inositol 1,4,5-trisphosphate, inositol 1,3,4,5-tetrakisphosphate, phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate.
ADGRG1	Adhesion G-protein coupled receptor G1	Adhesion G-protein coupled receptor (aGPCR) for steroid hormone 17alpha-hydroxypregnenolone (17-OH), which is involved in cell adhesion and cell-cell interactions.
AP4E1	AP-4 complex subunit epsilon-1	Component of the adaptor protein complex 4 (AP-4).
MTRR	Methionine synthase reductase	Key enzyme in methionine and folate homeostasis responsible for the reactivation of methionine synthase (MTR/MS) activity by catalyzing the reductive methylation of MTR-bound cob(II)alamin.
MYH7	Myosin-7	Myosins are actin-based motor molecules with ATPase activity essential for muscle contraction.
NEB	Nebulin	This giant muscle protein may be involved in maintaining the structural integrity of sarcomeres and the membrane system associated with the myofibrils.
OCRL	Inositol polyphosphate 5-phosphatase OCRL	Catalyzes the hydrolysis of the 5-position phosphate of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and phosphatidylinositol-3,4,5-bisphosphate (PtdIns(3,4,5)P3), with the greatest catalytic activity towards PtdIns(4,5)P2.

Protein-family classification

Druggable: 18 · Difficult: 5 · Unknown: 21 · Druggable fraction: 0.41

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	5	12.7×	4e-04
Complement	1	6.1×	0.498
Antibody/Immunoglobulin	3	2.0×	0.498
Kinase	3	1.9×	0.498
Scaffold/PPI	4	1.6×	0.498
Enzyme (other)	4	1.1×	0.843
Other/Unknown	21	0.9×	0.990
Protease	1	0.8×	0.990
GPCR	1	0.5×	0.990
Transcription factor	1	0.2×	0.997

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TNNT3	Other/Unknown	no		Troponin, TNNT, Troponin_sf
TTN	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ig_sub2, Ig_sub
CACNA1S	Ion channel	yes		VDCCAlpha1, VDCC_L_a1su, VDCC_L_a1ssu
COL6A6	Other/Unknown	no		VWF_A, Collagen, vWFA_dom_sf
FXR1	Complement	yes		KH_dom, KH_dom_type_1, Agenet-like_dom
RYR3	Ion channel	yes		RIH_dom, B30.2/SPRY, EF_hand_dom
SCN4A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a4su_mammal
TPM2	Other/Unknown	no		Tropomyosin
TUBA4A	Other/Unknown	no		Tubulin, Alpha_tubulin, Tubulin_FtsZ_GTPase
DNAJB4	Other/Unknown	no		DnaJ_domain, DnaJ_C, HSP40/DnaJ_pept-bd
GNE	Enzyme (other)	yes	2.7.1.60	ROK, UDP_GlcNAc_Epimerase_2_dom, UDP-GlcNAc_Epase
HACD1	Other/Unknown	no		Tyr_Pase-like_PTPLA
RYR1	Ion channel	yes		RIH_dom, B30.2/SPRY, Ryanodine_rcpt
SRPK3	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
SYT2	Other/Unknown	no		C2_dom, Synaptotagmin, C2_domain_sf
USP9X	Protease	yes		Peptidase_C19_UCH, ARM-type_fold, USP_CS
ACTA1	Other/Unknown	no		Actin, Actin_CS, Actin/actin-like_CS
MYO15B	Scaffold/PPI	no		FERM_domain, MyTH4_dom, SH3_domain
JPH1	Other/Unknown	no		MORN, Junctophilin
CBS	Enzyme (other)	yes	4.2.1.22	CBS_dom, P-phosphate_BS, TrpB-like_PALP
SPEG	Kinase	yes		Prot_kinase_dom, Ig_sub2, Ig_sub
EXOSC3	Other/Unknown	no		KH_dom_type_1, NA-bd_OB-fold, Exosome_RNA_bind1/RRP40/RRP4
TRPV4	Ion channel	yes		Ankyrin_rpt, Ion_trans_dom, TrpV1-4
ASCC3	Other/Unknown	no		Helicase_C-like, AAA+_ATPase, Sec63-dom
CHRNA1	Other/Unknown	no		Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel
ZFYVE26	Transcription factor	no		Znf_FYVE, Znf_FYVE_PHD, Znf_RING/FYVE/PHD
COL6A2	Other/Unknown	no		VWF_A, Collagen, vWFA_dom_sf
COL6A3	Antibody/Immunoglobulin	yes		VWF_A, Kunitz_BPTI, FN3_dom
MYPN	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom
KANSL1	Other/Unknown	no		NSL1, PEHE_dom
STAC3	Scaffold/PPI	no		SH3_domain, PKC_DAG/PE, Stac3_SH3_1
DNA2	Other/Unknown	no		PDDEXK-like_dom_sf, DNA_replication_fac_Dna2_N, Dna2/JHS1_DEXXQ-box
ALG13	Other/Unknown	no		Tudor, OTU_dom, Glyco_trans_28_C
INPP5K	Enzyme (other)	yes	3.1.3.56	IPPc, Endo/exonu/phosph_ase_sf, SKICH
SNHG14	Other/Unknown	no
ADGRG1	GPCR	yes		GPS, GPCR_2_secretin-like, GPR1/GPR3/GPR5
MHRT	Other/Unknown	no
TCF4-AS1	Other/Unknown	no
CNN3-DT	Other/Unknown	no
AP4E1	Other/Unknown	no		Clathrin/coatomer_adapt-like_N, ARM-like, ARM-type_fold
MTRR	Enzyme (other)	yes	1.16.1.8	Flavdoxin-like, OxRdtase_FAD/NAD-bd, Flavoprot_Pyr_Nucl_cyt_Rdtase
MYH7	Scaffold/PPI	no		IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Myosin_tail
NEB	Scaffold/PPI	no		Nebulin_repeat, SH3_domain, Nebulin-like
OCRL	Antibody/Immunoglobulin	yes	3.1.3.36	RhoGAP_dom, IPPc, Rho_GTPase_activation_prot

Expression context

Cohort genes with no expression data: 1.

37 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)	43
unknown	1

Top tissues across cohort

Tissue	Cohort genes
hindlimb stylopod muscle	9
gastrocnemius	8
gluteal muscle	7
skeletal muscle tissue of biceps brachii	4
secondary oocyte	4
sural nerve	3
calcaneal tendon	3
biceps brachii	2
buccal mucosa cell	2
diaphragm	2
skeletal muscle tissue of rectus abdominis	2
popliteal artery	2
gingival epithelium	2
pons	2
endometrium epithelium	2
right uterine tube	2
tibialis anterior	2
vastus lateralis	2
right coronary artery	2
muscle of leg	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TNNT3	135	broad	marker	hindlimb stylopod muscle, skeletal muscle tissue, gastrocnemius
TTN	223	broad	marker	biceps brachii, gluteal muscle, skeletal muscle tissue of biceps brachii
CACNA1S	105	tissue_specific	marker	gluteal muscle, hindlimb stylopod muscle, triceps brachii
COL6A6	140		marker	buccal mucosa cell, parietal pleura, cardiac muscle of right atrium
FXR1	299	ubiquitous	marker	sperm, hindlimb stylopod muscle, gastrocnemius
RYR3	233	broad	marker	diaphragm, sural nerve, right hemisphere of cerebellum
SCN4A	153	tissue_specific	yes	hindlimb stylopod muscle, gastrocnemius, skeletal muscle tissue of rectus abdominis
TPM2	283	ubiquitous	marker	saphenous vein, popliteal artery, blood vessel layer
TUBA4A	299	ubiquitous	marker	gingival epithelium, frontal pole, gingiva
DNAJB4	290	ubiquitous	marker	skeletal muscle tissue of rectus abdominis, calcaneal tendon, skeletal muscle tissue of biceps brachii
GNE	286	ubiquitous	marker	mucosa of sigmoid colon, colonic mucosa, nasal cavity epithelium
HACD1	257	ubiquitous	marker	heart right ventricle, heart left ventricle, cardiac ventricle
RYR1	214	broad	marker	gluteal muscle, gastrocnemius, hindlimb stylopod muscle
SRPK3	202	broad	marker	hindlimb stylopod muscle, gluteal muscle, gastrocnemius
SYT2	165	tissue_specific	yes	olfactory bulb, pons, type B pancreatic cell
USP9X	295	ubiquitous	marker	middle frontal gyrus, endometrium epithelium, secondary oocyte
ACTA1	203	broad	marker	gluteal muscle, skeletal muscle tissue of biceps brachii, diaphragm
MYO15B	228	broad	marker	right uterine tube, left ovary, right ovary
JPH1	213	broad	marker	quadriceps femoris, vastus lateralis, tibialis anterior
CBS	134	tissue_specific	marker	right lobe of liver, body of pancreas, liver
SPEG	249	ubiquitous	yes	popliteal artery, tibial artery, right coronary artery
EXOSC3	246	ubiquitous	marker	oocyte, secondary oocyte, tendon of biceps brachii
TRPV4	171	ubiquitous	marker	cartilage tissue, lower esophagus mucosa, olfactory segment of nasal mucosa
ASCC3	278	ubiquitous	marker	decidua, secondary oocyte, calcaneal tendon
CHRNA1	149	broad	marker	gastrocnemius, gluteal muscle, muscle of leg
ZFYVE26	287	ubiquitous	marker	sural nerve, endothelial cell, visceral pleura
COL6A2	263	ubiquitous	marker	stromal cell of endometrium, right coronary artery, descending thoracic aorta
COL6A3	264	broad	marker	stromal cell of endometrium, visceral pleura, skin of hip
MYPN	116	broad	marker	hindlimb stylopod muscle, gastrocnemius, vastus lateralis
KANSL1	250	ubiquitous	marker	bone marrow cell, colonic epithelium, thymus

Protein interactions among cohort

Intra-cohort edges: 17.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TTN	4,237
FXR1	4,128
USP9X	3,484
ASCC3	2,898
DNAJB4	2,877
DNA2	2,792
COL6A2	2,786
MYH7	2,744
EXOSC3	2,330
OCRL	2,269

Intra-cohort edges

A	B	Sources
CACNA1S	JPH1	string_interaction
CACNA1S	RYR1	string_interaction
CACNA1S	RYR3	string_interaction
CACNA1S	STAC3	string_interaction
COL6A2	COL6A3	string_interaction
COL6A2	COL6A6	string_interaction
JPH1	RYR1	string_interaction
JPH1	STAC3	string_interaction
MYH7	TPM2	biogrid_interaction
MYH7	TTN	string_interaction
MYPN	NEB	biogrid_interaction, string_interaction
MYPN	TTN	biogrid_interaction, string_interaction
NEB	TPM2	biogrid_interaction
NEB	TTN	intact, string_interaction
RYR1	STAC3	string_interaction
RYR1	TTN	intact
SCN4A	STAC3	string_interaction

Structural data

PDB: 31 · AlphaFold-only: 9 · No structure: 4

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TTN	Q8WZ42	64
MYH7	P12883	43
CBS	P35520	19
TRPV4	Q9HBA0	19
CHRNA1	P02708	15
RYR3	Q15413	10
EXOSC3	Q9NQT5	8
COL6A3	P12111	6
GNE	Q9Y223	5
ACTA1	P68133	5
STAC3	Q96MF2	5
OCRL	Q01968	5
USP9X	Q93008	4
AP4E1	Q9UPM8	4
FXR1	P51114	3
SCN4A	P35499	3
NEB	P20929	3
CACNA1S	Q13698	2
RYR1	P21817	2
ASCC3	Q8N3C0	2
KANSL1	Q7Z3B3	2
MTRR	Q9UBK8	2
SYT2	Q8N9I0	1
MYO15B	Q96JP2	1
JPH1	Q9HDC5	1
SPEG	Q15772	1
ZFYVE26	Q68DK2	1
COL6A2	P12110	1
DNA2	P51530	1
INPP5K	Q9BT40	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TUBA4A	P68366	92.02
TPM2	P07951	91.51
DNAJB4	Q9UDY4	83.43
SRPK3	Q9UPE1	80.61
TNNT3	P45378	77.99
HACD1	B0YJ81	77.13
COL6A6	A6NMZ7	75.61
ALG13	Q9NP73	54.42
MYPN	Q86TC9	52.71

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 215. Enrichment computed across 44 evidence-associated genes (30 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 30 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Striated Muscle Contraction	5	51.4×	8e-06	TNNT3, TTN, TPM2, ACTA1, NEB
NCAM1 interactions	4	33.1×	6e-04	CACNA1S, COL6A6, COL6A2, COL6A3
Muscle contraction	5	12.9×	0.003	RYR1, RYR3, SCN4A, ACTA1, NEB
Collagen chain trimerization	3	25.9×	0.009	COL6A6, COL6A2, COL6A3
Signaling by PDGF	3	25.4×	0.009	COL6A6, COL6A2, COL6A3
Assembly of collagen fibrils and other multimeric structures	3	20.0×	0.016	COL6A6, COL6A2, COL6A3
Collagen degradation	3	17.6×	0.019	COL6A6, COL6A2, COL6A3
Collagen biosynthesis and modifying enzymes	3	17.0×	0.019	COL6A6, COL6A2, COL6A3
ECM proteoglycans	3	15.0×	0.024	COL6A6, COL6A2, COL6A3
Sulfur amino acid metabolism	2	38.1×	0.026	CBS, MTRR
Integrin cell surface interactions	3	13.4×	0.027	COL6A6, COL6A2, COL6A3
Defective GNE causes sialuria, NK and IBM2	1	380.7×	0.043	GNE
Cardiac conduction	3	10.9×	0.043	RYR1, RYR3, SCN4A
Cysteine formation from homocysteine	1	190.3×	0.066	CBS
Defective MTRR causes HMAE	1	190.3×	0.066	MTRR
Defective MTR causes HMAG	1	190.3×	0.066	MTRR
Defective ALG14 causes ALG14-CMS	1	190.3×	0.066	ALG13
Toxicity of botulinum toxin type B (botB)	1	126.9×	0.094	SYT2
Synthesis of PIPs at the plasma membrane	2	14.1×	0.099	INPP5K, OCRL
Ion homeostasis	2	13.6×	0.100	RYR1, RYR3
Golgi Associated Vesicle Biogenesis	2	13.4×	0.100	AP4E1, OCRL
ALKBH3 mediated reversal of alkylation damage	1	95.2×	0.102	ASCC3
DNA Damage Reversal	1	54.4×	0.163	ASCC3
Reversal of alkylation damage by DNA dioxygenases	1	54.4×	0.163	ASCC3
Neurotoxicity of clostridium toxins	1	47.6×	0.166	SYT2
Metabolism of ingested SeMet, Sec, MeSec into H2Se	1	47.6×	0.166	CBS
Stimuli-sensing channels	2	9.1×	0.166	RYR1, RYR3
Highly calcium permeable nicotinic acetylcholine receptors	1	42.3×	0.174	CHRNA1
Cobalamin (Cbl) metabolism	1	42.3×	0.174	MTRR
Highly calcium permeable postsynaptic nicotinic acetylcholine receptors	1	34.6×	0.181	CHRNA1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 39 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
striated muscle contraction	5	108.0×	1e-07	TTN, CACNA1S, RYR1, RYR3, MYH7
muscle contraction	7	37.3×	1e-07	TTN, CACNA1S, RYR1, SCN4A, TPM2, ACTA1, MYH7
skeletal muscle contraction	5	65.5×	1e-06	TNNT3, TTN, CHRNA1, STAC3, MYH7
skeletal muscle fiber development	4	55.8×	6e-05	CACNA1S, RYR1, ACTA1, STAC3
cellular response to caffeine	3	117.8×	1e-04	CACNA1S, RYR1, RYR3
muscle organ development	5	21.4×	2e-04	FXR1, JPH1, SPEG, COL6A3, NEB
regulation of ATP-dependent activity	2	432.1×	2e-04	TNNT3, TPM2
L-homocysteine catabolic process	2	288.1×	6e-04	CBS, MTRR
calcium ion transport	4	18.6×	0.002	CACNA1S, RYR1, RYR3, TRPV4
skeletal muscle thin filament assembly	2	144.0×	0.003	TTN, ACTA1
cartilage development involved in endochondral bone morphogenesis	2	123.5×	0.003	CBS, TRPV4
sarcomere organization	3	29.5×	0.004	TNNT3, TTN, MYPN
homocysteine metabolic process	2	96.0×	0.005	CBS, MTRR
release of sequestered calcium ion into cytosol	3	26.5×	0.005	CACNA1S, RYR1, RYR3
release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	2	86.4×	0.005	RYR1, RYR3
DNA alkylation repair	2	78.6×	0.006	USP9X, ASCC3
muscle filament sliding	2	54.0×	0.012	TTN, MYH7
calcium ion transmembrane transport	3	16.2×	0.015	CACNA1S, RYR3, TRPV4
obsolete L-cysteine biosynthetic process from L-serine	1	432.1×	0.026	CBS
DNA replication, Okazaki fragment processing	1	432.1×	0.026	DNA2
hyperosmotic salinity response	1	432.1×	0.026	TRPV4
skeletal muscle adaptation	1	432.1×	0.026	CACNA1S
blood vessel endothelial cell delamination	1	432.1×	0.026	TRPV4
regulation of skeletal muscle contraction by action potential	1	432.1×	0.026	SCN4A
positive regulation of calcium-dependent ATPase activity	1	432.1×	0.026	TNNT3
positive regulation of renal water transport	1	432.1×	0.026	INPP5K
phosphatidylinositol dephosphorylation	2	33.2×	0.026	INPP5K, OCRL
neuromuscular synaptic transmission	2	30.9×	0.026	CHRNA1, STAC3
positive regulation of Rho protein signal transduction	2	29.8×	0.026	FXR1, ADGRG1
calcium ion import across plasma membrane	2	27.9×	0.026	CACNA1S, TRPV4

Therapeutics

Drug target analysis

Approved (phase 4): 5 · Phase ≥3: 7 · Phased (≥1): 8 · Undrugged: 36

Druggability breadth: 20 of 44 evidence-associated genes (45%) 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
CACNA1S	BEPRIDIL
SCN4A	CARBAMAZEPINE
TUBA4A	COLCHICINE
SRPK3	FEDRATINIB
CHRNA1	VARENICLINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CACNA1S	48	4
SCN4A	24	4
TUBA4A	22	4
SRPK3	18	4
CHRNA1	12	4
TRPV4	6	3
USP9X	1	2
CBS	1	3
TNNT3	0	0
TTN	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	CACNA1S
IMIPRAMINE	4	CACNA1S, SCN4A
HALOFANTRINE	4	CACNA1S
DROPERIDOL	4	CACNA1S
SAQUINAVIR	4	CACNA1S
DULOXETINE	4	CACNA1S
DIAZEPAM	4	CACNA1S
SERTINDOLE	4	CACNA1S, SCN4A
QUINIDINE	4	CACNA1S
LAMIVUDINE	4	CACNA1S
PIMOZIDE	4	CACNA1S, SCN4A
PHENYTOIN	4	CACNA1S, SCN4A
TERFENADINE	4	CACNA1S
CISAPRIDE	4	CACNA1S
SOLIFENACIN	4	CACNA1S
NIFEDIPINE	4	CACNA1S, SCN4A
DILTIAZEM	4	CACNA1S, SCN4A
NILOTINIB	4	CACNA1S
ASTEMIZOLE	4	CACNA1S
TERODILINE	4	CACNA1S
CLOZAPINE	4	CACNA1S
MIBEFRADIL	4	CACNA1S, SCN4A
DOFETILIDE	4	CACNA1S
THIORIDAZINE	4	CACNA1S
PAROXETINE	4	CACNA1S
DONEPEZIL	4	CACNA1S
IBUTILIDE	4	CACNA1S
SUNITINIB	4	CACNA1S, SRPK3
HALOPERIDOL	4	CACNA1S, SCN4A
DASATINIB	4	CACNA1S

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 7.

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

Symbol	Assays	Type breakdown
TUBA4A	1,695	Binding:1654, Functional:35, ADMET:6
SRPK3	229	Binding:229
CACNA1S	228	Binding:142, Functional:79, Toxicity:5, ADMET:2
CHRNA1	157	Binding:107, Functional:47, ADMET:2, Toxicity:1
TRPV4	99	Binding:94, Functional:5
SCN4A	95	Binding:69, Functional:18, ADMET:7, Toxicity:1
USP9X	41	Binding:41
DNA2	23	Binding:23
CBS	22	Binding:22
RYR1	16	Binding:13, Functional:3
FXR1	6	Binding:6
ADGRG1	3	Binding:3
RYR3	2	Binding:2
TTN	1	Binding:1
GNE	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TTN	2.7.11.1	non-specific serine/threonine protein kinase
GNE	2.7.1.60, 3.2.1.183, 5.1.3.14	N-acylmannosamine kinase, UDP-N-acetylglucosamine 2-epimerase (hydrolysing), UDP-N-acetylglucosamine 2-epimerase (non-hydrolysing)
SRPK3	2.7.11.1	non-specific serine/threonine protein kinase
CBS	4.2.1.22	cystathionine beta-synthase
INPP5K	3.1.3.56	inositol-polyphosphate 5-phosphatase
MTRR	1.16.1.8	[methionine synthase] reductase
OCRL	3.1.3.36	phosphoinositide 5-phosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CACNA1S	228
TUBA4A	1,695
SRPK3	229
CHRNA1	157

Pharmacogenomics

Cohort genes with a PharmGKB record: 40; with CPIC/DPWG dosing guidelines: 2.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
CACNA1S	1
RYR1	1

Chemical tractability of cohort targets

30 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)
BEPRIDIL	4	CACNA1S
IMIPRAMINE	4	CACNA1S, SCN4A
HALOFANTRINE	4	CACNA1S
DROPERIDOL	4	CACNA1S
SAQUINAVIR	4	CACNA1S
DULOXETINE	4	CACNA1S
DIAZEPAM	4	CACNA1S
SERTINDOLE	4	CACNA1S, SCN4A
QUINIDINE	4	CACNA1S
LAMIVUDINE	4	CACNA1S
PIMOZIDE	4	CACNA1S, SCN4A
PHENYTOIN	4	CACNA1S, SCN4A
TERFENADINE	4	CACNA1S
CISAPRIDE	4	CACNA1S
SOLIFENACIN	4	CACNA1S
NIFEDIPINE	4	CACNA1S, SCN4A
DILTIAZEM	4	CACNA1S, SCN4A
NILOTINIB	4	CACNA1S
ASTEMIZOLE	4	CACNA1S
TERODILINE	4	CACNA1S
CLOZAPINE	4	CACNA1S
MIBEFRADIL	4	CACNA1S, SCN4A
DOFETILIDE	4	CACNA1S
THIORIDAZINE	4	CACNA1S
PAROXETINE	4	CACNA1S
DONEPEZIL	4	CACNA1S
IBUTILIDE	4	CACNA1S
SUNITINIB	4	CACNA1S, SRPK3
HALOPERIDOL	4	CACNA1S, SCN4A
DASATINIB	4	CACNA1S

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	5	CACNA1S, SCN4A, TUBA4A, SRPK3, CHRNA1
B	Phased (≥1) drug, not yet approved	3	USP9X, CBS, TRPV4
C	Druggable family + PDB, no drug	11	TTN, FXR1, RYR3, GNE, RYR1, SPEG, COL6A3, INPP5K, ADGRG1, MTRR (+1 more)
D	Druggable family + AlphaFold only, no drug	1	MYPN
E	Difficult family or no structure, no drug	24	TNNT3, COL6A6, TPM2, DNAJB4, HACD1, SYT2, ACTA1, MYO15B, JPH1, EXOSC3 (+14 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
STAC3	0	CACNA1S
TNNT3	0	—
TTN	1	—
COL6A6	0	—
FXR1	6	—
RYR3	2	—
TPM2	0	—
DNAJB4	0	—
GNE	1	—
HACD1	0	—
RYR1	16	—
SYT2	0	—
ACTA1	0	—
MYO15B	0	—
JPH1	0	—
SPEG	0	—
EXOSC3	0	—
ASCC3	0	—
ZFYVE26	0	—
COL6A2	0	—
COL6A3	0	—
MYPN	0	—
KANSL1	0	—
DNA2	23	—
ALG13	0	—
INPP5K	0	—
SNHG14	0	—
ADGRG1	3	—
MHRT	0	—
TCF4-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 13.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	13

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06791369	Not specified	NOT_YET_RECRUITING	The Prevalence of RYR1-related Disease
NCT06833489	Not specified	RECRUITING	Transcriptomic Analysis to Put an End to Misdiagnosis in Patients With Rare Muscle Diseases
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