Dystonic disorder

Summary

Dystonic disorder (MONDO:0003441) is a disease (an umbrella term covering 8 Mondo subtypes) with 45 cohort genes and 169 clinical trials. Top therapeutic interventions include trihexyphenidyl, amantadine, and ampicillin.

At a glance

• Umbrella term: 8 Mondo subtypes
• Cohort genes: 45
• ClinVar variants: 1,335
• Clinical trials: 169

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	dystonic disorder
Mondo ID	MONDO:0003441
MeSH	D020821
DOID	DOID:543
ICD-10-CM	G24
NCIT	C34563
SNOMED CT	15802004
UMLS	C0013421
MedGen	3940
GARD	0027640
Is cancer (heuristic)	no

Also known as: dystonia · dystonia disorder · dystonia disorders · dystonic disorder

Data availability: 1,335 ClinVar variants · 1 HPO phenotype · 35 cell lines.

Disease family

An umbrella term covering 8 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › movement disorder › extrapyramidal and movement disease › dystonic disorder

Subtypes (8): focal dystonia, multifocal dystonia, segmental dystonia, hemidystonia-hemiatrophy syndrome, nocturnal paroxysmal dystonia, inherited dystonia, idiopathic torsion dystonia, torsion dystonia

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

245 uncertain significance, 218 likely benign, 74 benign, 21 conflicting classifications of pathogenicity, 17 pathogenic, 12 benign/likely benign, 9 likely pathogenic, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2159492	NM_031418.4(ANO3):c.1952G>A (p.Ser651Asn)	ANO3	Pathogenic	criteria provided, single submitter
1697211	NM_001659.3(ARF3):c.200A>T (p.Asp67Val)	ARF3	Pathogenic	criteria provided, single submitter
2424629	NC_000002.11:g.(?71004499)(74779761_?)del	C2orf78	Pathogenic	criteria provided, single submitter
265316	NM_001367721.1(CASK):c.2521-2A>G	CASK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1460398	NC_000018.9:g.(?11752433)(11881134_?)del	CHMP1B	Pathogenic	criteria provided, single submitter
1687225	NM_000161.3(GCH1):c.478A>T (p.Lys160Ter)	GCH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451598	NM_001369387.1(GNAL):c.55_64dup (p.Arg22fs)	GNAL	Pathogenic	criteria provided, single submitter
1454252	NM_001369387.1(GNAL):c.91C>T (p.Gln31Ter)	GNAL	Pathogenic	criteria provided, single submitter
1457837	NM_182978.4(GNAL):c.710_713del (p.Asp237fs)	GNAL	Pathogenic	criteria provided, single submitter
2138127	NM_182978.4(GNAL):c.667G>A (p.Val223Met)	GNAL	Pathogenic	criteria provided, single submitter
2138128	NM_182978.4(GNAL):c.1292T>C (p.Val431Ala)	GNAL	Pathogenic	criteria provided, single submitter
208722	NM_002074.5(GNB1):c.239T>C (p.Ile80Thr)	GNB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
242881	NM_001382347.1(MYO5A):c.4200C>G (p.Ser1400Arg)	MYO5A	Pathogenic	no assertion criteria provided
12941	NM_003124.5(SPR):c.448A>G (p.Arg150Gly)	SPR	Pathogenic	criteria provided, multiple submitters, no conflicts
12944	NM_003124.5(SPR):c.751A>T (p.Lys251Ter)	SPR	Pathogenic	criteria provided, multiple submitters, no conflicts
1323647	NM_003124.5(SPR):c.544C>T (p.Gln182Ter)	SPR	Pathogenic	criteria provided, multiple submitters, no conflicts
1458146	NC_000002.11:g.(?73114562)(73115753_?)del	SPR	Pathogenic	criteria provided, single submitter
2165411	NM_003124.5(SPR):c.277C>T (p.Gln93Ter)	SPR	Pathogenic	criteria provided, single submitter
2197705	NM_003124.5(SPR):c.688A>T (p.Lys230Ter)	SPR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
235551	NM_003124.5(SPR):c.655C>T (p.Arg219Ter)	SPR	Pathogenic	criteria provided, multiple submitters, no conflicts
2720176	NM_003124.5(SPR):c.715C>T (p.Gln239Ter)	SPR	Pathogenic	criteria provided, multiple submitters, no conflicts
1185004	NM_024063.3(AFG2B):c.[213T>G;1313T>C]		Likely pathogenic	criteria provided, single submitter
1697208	NM_001659.3(ARF3):c.34C>G (p.Leu12Val)	ARF3	Likely pathogenic	criteria provided, single submitter
1043845	NM_001369387.1(GNAL):c.37G>T (p.Asp13Tyr)	GNAL	Likely pathogenic	criteria provided, single submitter
1164002	NM_000884.3(IMPDH2):c.93_96del (p.Tyr32fs)	IMPDH2	Likely pathogenic	no assertion criteria provided
1803982	NM_000884.3(IMPDH2):c.338G>A (p.Gly113Glu)	IMPDH2	Likely pathogenic	criteria provided, single submitter
1184812	NM_014727.3(KMT2B):c.6439C>T (p.Gln2147Ter)	KMT2B	Likely pathogenic	no assertion criteria provided
209173	NC_012920.1(MT-ND6):m.14597A>G	MT-ND6	Likely pathogenic	reviewed by expert panel
1162323	NM_003124.5(SPR):c.512G>A (p.Cys171Tyr)	SPR	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1414432	NM_003124.5(SPR):c.596-2_602del	SPR	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 93 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SPR	Orphanet:70594	Dopa-responsive dystonia due to sepiapterin reductase deficiency
TH	Orphanet:101150	Autosomal recessive dopa-responsive dystonia
ACTB	Orphanet:2995	Baraitser-Winter cerebrofrontofacial syndrome
ACTB	Orphanet:64755	Becker nevus syndrome
ACTB	Orphanet:673556	Pseudomyogenic hemangioendothelioma
ACTB	Orphanet:674653	Actinomyopathy-associated syndromic thrombocytopenia
ACTB	Orphanet:79107	Developmental malformations-deafness-dystonia syndrome
ANO3	Orphanet:420485	Cranio-cervical dystonia with laryngeal and upper-limb involvement
CAMK2B	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
CASK	Orphanet:163937	X-linked intellectual disability, Najm type
CASK	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
CASK	Orphanet:777	X-linked non-syndromic intellectual disability
KMT2B	Orphanet:528084	Non-specific syndromic intellectual disability
KMT2B	Orphanet:589618	Dystonia 28
PANK2	Orphanet:216866	Classic pantothenate kinase-associated neurodegeneration
PANK2	Orphanet:216873	Atypical pantothenate kinase-associated neurodegeneration
CIZ1	Orphanet:420492	Adult-onset cervical dystonia, DYT23 type
GJC2	Orphanet:280282	Pelizaeus-Merzbacher-like disease due to GJC2 mutation
GJC2	Orphanet:320401	Autosomal recessive spastic paraplegia type 44
GJC2	Orphanet:568051	GJC2-related late-onset primary lymphedema
RHOBTB2	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
RHOBTB2	Orphanet:2131	Alternating hemiplegia of childhood
THAP1	Orphanet:98806	Primary dystonia, DYT6 type
SATB2	Orphanet:251019	2q32q33 deletion syndrome
SATB2	Orphanet:251028	SATB2-associated syndrome due to a chromosomal rearrangement
SATB2	Orphanet:576283	SATB2-associated syndrome due to a pathogenic variant
CSTB	Orphanet:248	Autosomal recessive hypohidrotic ectodermal dysplasia
CSTB	Orphanet:308	Progressive myoclonic epilepsy type 1
CEP104	Orphanet:475	Isolated Joubert syndrome
CEP104	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
C19orf12	Orphanet:289560	Mitochondrial membrane protein-associated neurodegeneration
C19orf12	Orphanet:320370	Autosomal recessive spastic paraplegia type 43
WDR73	Orphanet:2065	Galloway-Mowat syndrome
WDR73	Orphanet:83472	CAMOS syndrome
DCTN1	Orphanet:139589	Distal hereditary motor neuropathy type 7
DCTN1	Orphanet:178509	Perry syndrome
DCTN1	Orphanet:803	Amyotrophic lateral sclerosis
DRD2	Orphanet:36899	Myoclonus-dystonia syndrome
TOR1A	Orphanet:256	Early-onset generalized limb-onset dystonia
TOR1A	Orphanet:36899	Myoclonus-dystonia syndrome
AFG3L2	Orphanet:101109	Spinocerebellar ataxia type 28
AFG3L2	Orphanet:313772	Early-onset spastic ataxia-myoclonic epilepsy-neuropathy syndrome
FUS	Orphanet:275872	Frontotemporal dementia with motor neuron disease
FUS	Orphanet:300605	Juvenile amyotrophic lateral sclerosis
FUS	Orphanet:79105	Myxofibrosarcoma
FUS	Orphanet:803	Amyotrophic lateral sclerosis
FUS	Orphanet:99967	Myxoid/round cell liposarcoma
GCH1	Orphanet:2102	GTP cyclohydrolase I deficiency
GCH1	Orphanet:98808	Autosomal dominant dopa-responsive dystonia
GNAL	Orphanet:329466	Autosomal dominant focal dystonia, DYT25 type

Cohort genes → proteins

45 cohort genes, 45 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	45

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SPR	HGNC:11257	ENSG00000116096	P35270	Sepiapterin reductase	clinvar
TACR1	HGNC:11526	ENSG00000115353	P25103	Substance-P receptor	clinvar
TH	HGNC:11782	ENSG00000180176	P07101	Tyrosine 3-monooxygenase	clinvar
ACTB	HGNC:132	ENSG00000075624	P60709	Actin, cytoplasmic 1	clinvar
ANO3	HGNC:14004	ENSG00000134343	Q9BYT9	Anoctamin-3	clinvar
CAMK2B	HGNC:1461	ENSG00000058404	Q13554	Calcium/calmodulin-dependent protein kinase type II subunit beta	clinvar
CASK	HGNC:1497	ENSG00000147044	O14936	Peripheral plasma membrane protein CASK	clinvar
KMT2B	HGNC:15840	ENSG00000272333	Q9UMN6	Histone-lysine N-methyltransferase 2B	clinvar
PANK2	HGNC:15894	ENSG00000125779	Q9BZ23	Pantothenate kinase 2, mitochondrial	clinvar
CIZ1	HGNC:16744	ENSG00000148337	Q9ULV3	Cip1-interacting zinc finger protein	clinvar
GJC2	HGNC:17494	ENSG00000198835	Q5T442	Gap junction gamma-2 protein	clinvar
RHOBTB2	HGNC:18756	ENSG00000008853	Q9BYZ6	Rho-related BTB domain-containing protein 2	clinvar
THAP1	HGNC:20856	ENSG00000131931	Q9NVV9	THAP domain-containing protein 1	clinvar
ARFGEF3	HGNC:21213	ENSG00000112379	Q5TH69	Brefeldin A-inhibited guanine nucleotide-exchange protein 3	clinvar
SATB2	HGNC:21637	ENSG00000119042	Q9UPW6	DNA-binding protein SATB2	clinvar
NTMT1	HGNC:23373	ENSG00000148335	Q9BV86	N-terminal Xaa-Pro-Lys N-methyltransferase 1	clinvar
CHMP1B	HGNC:24287	ENSG00000255112	Q7LBR1	Charged multivesicular body protein 1b	clinvar
CSTB	HGNC:2482	ENSG00000160213	P04080	Cystatin-B	clinvar
CEP104	HGNC:24866	ENSG00000116198	O60308	Centrosomal protein of 104 kDa	clinvar
PNPLA4	HGNC:24887	ENSG00000006757	P41247	Patatin-like phospholipase domain-containing protein 4	clinvar
C19orf12	HGNC:25443	ENSG00000131943	Q9NSK7	Protein C19orf12	clinvar
WDR73	HGNC:25928	ENSG00000177082	Q6P4I2	Integrator complex assembly factor WDR73	clinvar
DCTN1	HGNC:2711	ENSG00000204843	Q14203	Dynactin subunit 1	clinvar
DRD2	HGNC:3023	ENSG00000149295	P14416	D(2) dopamine receptor	clinvar
TOR1A	HGNC:3098	ENSG00000136827	O14656	Torsin-1A	clinvar
AFG3L2	HGNC:315	ENSG00000141385	Q9Y4W6	Mitochondrial inner membrane m-AAA protease component AFG3L2	clinvar
C2orf78	HGNC:34349	ENSG00000187833	A6NCI8	Uncharacterized protein C2orf78	clinvar
FUS	HGNC:4010	ENSG00000089280	P35637	RNA-binding protein FUS	clinvar
GCH1	HGNC:4193	ENSG00000131979	P30793	GTP cyclohydrolase 1	clinvar
GNAL	HGNC:4388	ENSG00000141404	P38405	Guanine nucleotide-binding protein G(olf) subunit alpha	clinvar
GNB1	HGNC:4396	ENSG00000078369	P62873	Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1	clinvar
SETX	HGNC:445	ENSG00000107290	Q7Z333	Helicase senataxin	clinvar
GRIA3	HGNC:4573	ENSG00000125675	P42263	Glutamate receptor 3	clinvar
IMPDH2	HGNC:6053	ENSG00000178035	P12268	Inosine-5’-monophosphate dehydrogenase 2	clinvar
ARF3	HGNC:654	ENSG00000134287	P61204	ADP-ribosylation factor 3	clinvar
MECP2	HGNC:6990	ENSG00000169057	P51608	Methyl-CpG-binding protein 2	clinvar
MRE11	HGNC:7230	ENSG00000020922	P49959	Double-strand break repair protein MRE11	clinvar
MT-ND1	HGNC:7455	ENSG00000198888	P03886	NADH-ubiquinone oxidoreductase chain 1	clinvar
MT-ND4	HGNC:7459	ENSG00000198886	C0HME5	Mitochondrial alternative ND4 protein	clinvar
MT-ND6	HGNC:7462	ENSG00000198695	P03923	NADH-ubiquinone oxidoreductase chain 6	clinvar
MYO5A	HGNC:7602	ENSG00000197535	Q9Y4I1	Unconventional myosin-Va	clinvar
NPC1	HGNC:7897	ENSG00000141458	O15118	NPC intracellular cholesterol transporter 1	clinvar
ATP1A3	HGNC:801	ENSG00000105409	P13637	Sodium/potassium-transporting ATPase subunit alpha-3	clinvar
ATP4A	HGNC:819	ENSG00000105675	P20648	Potassium-transporting ATPase alpha chain 1	clinvar
PCDH12	HGNC:8657	ENSG00000113555	Q9NPG4	Protocadherin-12	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SPR	Sepiapterin reductase	Catalyzes the final one or two reductions in tetra-hydrobiopterin biosynthesis to form 5,6,7,8-tetrahydrobiopterin.
TACR1	Substance-P receptor	Receptor for the tachykinin substance P, also able to bind and respond to tachynins neurokinin A/substance K and neurokinin B/neuromedin-K.
TH	Tyrosine 3-monooxygenase	Catalyzes the conversion of L-tyrosine to L-dihydroxyphenylalanine (L-Dopa), the rate-limiting step in the biosynthesis of catecholamines, dopamine, noradrenaline, and adrenaline.
ACTB	Actin, cytoplasmic 1	Actin is a highly conserved protein that polymerizes to produce filaments that form cross-linked networks in the cytoplasm of cells.
ANO3	Anoctamin-3	Has calcium-dependent phospholipid scramblase activity; scrambles phosphatidylcholine and galactosylceramide.
CAMK2B	Calcium/calmodulin-dependent protein kinase type II subunit beta	Calcium/calmodulin-dependent protein kinase that functions autonomously after Ca(2+)/calmodulin-binding and autophosphorylation, and is involved in dendritic spine and synapse formation, neuronal plasticity and regulation of sarcoplasmic r…
CASK	Peripheral plasma membrane protein CASK	Multidomain scaffolding Mg(2+)-independent protein kinase that catalyzes the phosphotransfer from ATP to proteins such as NRXN1, and plays a role in synaptic transmembrane protein anchoring and ion channel trafficking.
KMT2B	Histone-lysine N-methyltransferase 2B	Histone methyltransferase that catalyzes methyl group transfer from S-adenosyl-L-methionine to the epsilon-amino group of ‘Lys-4’ of histone H3 (H3K4) via a non-processive mechanism.
PANK2	Pantothenate kinase 2, mitochondrial	Mitochondrial isoform that catalyzes the phosphorylation of pantothenate to generate 4’-phosphopantothenate in the first and rate-determining step of coenzyme A (CoA) synthesis.
CIZ1	Cip1-interacting zinc finger protein	May regulate the subcellular localization of CIP/WAF1.
GJC2	Gap junction gamma-2 protein	One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.
RHOBTB2	Rho-related BTB domain-containing protein 2	Regulator of cell proliferation and apoptosis.
THAP1	THAP domain-containing protein 1	DNA-binding transcription regulator that regulates endothelial cell proliferation and G1/S cell-cycle progression.
ARFGEF3	Brefeldin A-inhibited guanine nucleotide-exchange protein 3	Participates in the regulation of systemic glucose homeostasis, where it negatively regulates insulin granule biogenesis in pancreatic islet beta cells.
SATB2	DNA-binding protein SATB2	Binds to DNA, at nuclear matrix- or scaffold-associated regions.
NTMT1	N-terminal Xaa-Pro-Lys N-methyltransferase 1	Distributive alpha-N-methyltransferase that methylates the N-terminus of target proteins containing the N-terminal motif [Ala/Gly/Pro/Ser]-Pro-Lys when the initiator Met is cleaved.
CHMP1B	Charged multivesicular body protein 1b	Probable peripherally associated component of the endosomal sorting required for transport complex III (ESCRT-III) which is involved in multivesicular bodies (MVBs) formation and sorting of endosomal cargo proteins into MVBs.
CSTB	Cystatin-B	This is an intracellular thiol proteinase inhibitor.
CEP104	Centrosomal protein of 104 kDa	Required for ciliogenesis and for structural integrity at the ciliary tip.
PNPLA4	Patatin-like phospholipase domain-containing protein 4	Has abundant triacylglycerol lipase activity.
WDR73	Integrator complex assembly factor WDR73	Component of a multiprotein complex required for the assembly of the RNA endonuclease module of the integrator complex.
DCTN1	Dynactin subunit 1	Part of the dynactin complex that activates the molecular motor dynein for ultra-processive transport along microtubules.
DRD2	D(2) dopamine receptor	Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase.
TOR1A	Torsin-1A	Protein with chaperone functions important for the control of protein folding, processing, stability and localization as well as for the reduction of misfolded protein aggregates.
AFG3L2	Mitochondrial inner membrane m-AAA protease component AFG3L2	Catalytic component of the m-AAA protease, a protease that plays a key role in proteostasis of inner mitochondrial membrane proteins, and which is essential for axonal and neuron development.
FUS	RNA-binding protein FUS	DNA/RNA-binding protein that plays a role in various cellular processes such as transcription regulation, RNA splicing, RNA transport, DNA repair and damage response.
GCH1	GTP cyclohydrolase 1	Positively regulates nitric oxide synthesis in umbilical vein endothelial cells (HUVECs).
GNAL	Guanine nucleotide-binding protein G(olf) subunit alpha	Guanine nucleotide-binding protein (G protein) involved as transducer in olfactory signal transduction controlled by G protein-coupled receptors (GPCRs).
GNB1	Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1	Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems.
SETX	Helicase senataxin	ATP-dependent 5’->3’ DNA/RNA helicase that preferentially unwinds RNA substrates over DNA, playing a crucial role in resolving R-loops and promoting transcription termination.
GRIA3	Glutamate receptor 3	Ionotropic glutamate receptor that functions as a ligand-gated cation channel, gated by L-glutamate and glutamatergic agonists such as alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), quisqualic acid, and kainic acid.
IMPDH2	Inosine-5’-monophosphate dehydrogenase 2	Catalyzes the conversion of inosine 5’-phosphate (IMP) to xanthosine 5’-phosphate (XMP), the first committed and rate-limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of…
ARF3	ADP-ribosylation factor 3	GTP-binding protein that functions as an allosteric activator of the cholera toxin catalytic subunit, an ADP-ribosyltransferase.
MECP2	Methyl-CpG-binding protein 2	Chromosomal protein that binds to methylated DNA.
MRE11	Double-strand break repair protein MRE11	Core component of the MRN complex, which plays a central role in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity and meiosis.
MT-ND1	NADH-ubiquinone oxidoreductase chain 1	Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor.
MT-ND4	Mitochondrial alternative ND4 protein	Regulates mitochondrial respiration by decreasing oxygen consumption.
MT-ND6	NADH-ubiquinone oxidoreductase chain 6	Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor.
MYO5A	Unconventional myosin-Va	Processive actin-based motor that can move in large steps approximating the 36-nm pseudo-repeat of the actin filament.
NPC1	NPC intracellular cholesterol transporter 1	Intracellular cholesterol transporter which acts in concert with NPC2 and plays an important role in the egress of cholesterol from the endosomal/lysosomal compartment.
ATP1A3	Sodium/potassium-transporting ATPase subunit alpha-3	This is the catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane.
ATP4A	Potassium-transporting ATPase alpha chain 1	The catalytic subunit of the gastric H(+)/K(+) ATPase pump which transports H(+) ions in exchange for K(+) ions across the apical membrane of parietal cells.
PCDH12	Protocadherin-12	Cellular adhesion molecule that may play an important role in cell-cell interactions at interendothelial junctions.

Protein-family classification

Druggable: 11 · Difficult: 11 · Unknown: 23 · Druggable fraction: 0.24

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
Enzyme (other)	6	1.6×	0.600
Transcription factor	8	1.5×	0.600
Kinase	2	1.2×	0.785
Scaffold/PPI	3	1.1×	0.785
GPCR	2	1.1×	0.785
Other/Unknown	23	0.9×	0.785
Protease	1	0.8×	0.785

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SPR	Enzyme (other)	yes	1.1.1.153	SDR_fam, Sepiapterin_red, NAD(P)-bd_dom_sf
TACR1	GPCR	yes		NK1_rcpt, GPCR_Rhodpsn, Neurokn_rcpt
TH	Enzyme (other)	yes	1.14.16.2	ArAA_hydroxylase, Tyr_3_mOase, ArAA_hydroxylase_Fe/CU_BS
ACTB	Other/Unknown	no		Actin, Actin_CS, Actin/actin-like_CS
ANO3	Other/Unknown	no		Anoctamin, Anoct_dimer, Anoctamin_TM
CAMK2B	Kinase	yes	2.7.11.17	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
CASK	Kinase	yes	2.7.11.1	Prot_kinase_dom, SH3_domain, PDZ
KMT2B	Transcription factor	no		SET_dom, Znf_PHD, Znf_CXXC
PANK2	Enzyme (other)	yes	2.7.1.33	Type_II_PanK, ATPase_NBD
CIZ1	Transcription factor	no		Matrin/U1-C_Znf_C2H2, Matrin/U1-like-C_Znf_C2H2, Znf_C2H2_type
GJC2	Other/Unknown	no		Connexin, Connexin_N, Connexin_CS
RHOBTB2	Other/Unknown	no		BTB/POZ_dom, Small_GTPase, Small_GTPase_Rho
THAP1	Transcription factor	no		THAP_Znf, THAP1/10, THAP_Znf_sf
ARFGEF3	Other/Unknown	no		Sec7_dom, Mon2/Sec7/BIG1-like_HDS, ARM-type_fold
SATB2	Transcription factor	no		HD, CUT_dom, Homeodomain-like_sf
NTMT1	Enzyme (other)	yes	2.1.1.244	MeTrfase_NTM1, SAM-dependent_MTases_sf
CHMP1B	Other/Unknown	no		Snf7_fam
CSTB	Other/Unknown	no		Cystatin_dom, Prot_inh_stefin, Prot_inh_cystat_CS
CEP104	Transcription factor	no		Galactose-bd-like_sf, ARM-like, ARM-type_fold
PNPLA4	Other/Unknown	no		PNPLA_dom, Acyl_Trfase/lysoPLipase, PLPL
C19orf12	Other/Unknown	no		C19orf12
WDR73	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_dom_sf
DCTN1	Other/Unknown	no		CAP-Gly_domain, Dynactin, CAP-Gly_dom_sf
DRD2	GPCR	yes		GPCR_Rhodpsn, Dopamine_rcpt, Dopamine_D2_rcpt
TOR1A	Other/Unknown	no		Torsin, Torsin_1/2, P-loop_NTPase
AFG3L2	Protease	yes	3.4.24.B18	Peptidase_M41, AAA+_ATPase, ATPase_AAA_core
C2orf78	Other/Unknown	no		DUF4629, C2orf78-like
FUS	Transcription factor	no		RRM_dom, Znf_RanBP2, Nucleotide-bd_a/b_plait_sf
GCH1	Enzyme (other)	yes	3.5.4.16	GTP_CycHdrlase_I, GTP_CycHdrlase_I_CS, GTP_CycHdrlase_I_dom
GNAL	Other/Unknown	no		Gprotein_alpha_S, Gprotein_alpha_su, GproteinA_insert
GNB1	Scaffold/PPI	no		WD40_G-protein_beta-like, WD40_rpt, WD40/YVTN_repeat-like_dom_sf
SETX	Other/Unknown	no		P-loop_NTPase, DNA2/NAM7_AAA_11, DNA2/NAM7-like_C
GRIA3	Other/Unknown	no		Iontro_rcpt_C, Iono_Glu_rcpt_met, ANF_lig-bd_rcpt
IMPDH2	Enzyme (other)	yes	1.1.1.205	CBS_dom, IMP_DH_GMPRt, IMP_DH
ARF3	Other/Unknown	no		Small_GTP-bd, Small_GTPase_ARF/SAR, Small_GTPase_ARF
MECP2	Other/Unknown	no		Methyl_CpG_DNA-bd, DNA-bd_dom_sf, Me_CpG-bd_MeCP2
MRE11	Other/Unknown	no		Mre11, Calcineurin-like_PHP, Mre11_DNA-bd
MT-ND1	Other/Unknown	no		NADH_UbQ_OxRdtase_su1/FPO, NADH_UbQ_OxRdtase_su1_CS
MT-ND4	Other/Unknown	no		NADH4_N, ND/Mrp_TM, NADH_UbQ_OxRdtase
MT-ND6	Other/Unknown	no		NADH_UbQ/plastoQ_OxRdtase_su6, ComplexI_Subunit6
MYO5A	Scaffold/PPI	no		IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Dilute_dom
NPC1	Other/Unknown	no		SSD, NPC1-like, NPC1_N
ATP1A3	Transcription factor	no		P_typ_ATPase, ATPase_P-typ_cation-transptr_N, P-type_ATPase_IIC
ATP4A	Transcription factor	no	7.2.2.19	P_typ_ATPase, ATPase_P-typ_cation-transptr_N, P-type_ATPase_IIC
PCDH12	Other/Unknown	no		Cadherin-like_dom, Cadherin_N, Cadherin-like_sf

Expression context

Cohort genes with no expression data: 0.

42 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)	1
broad (>20)	44
unknown	0

Top tissues across cohort

Tissue	Cohort genes
secondary oocyte	7
male germ line stem cell (sensu Vertebrata) in testis	5
right testis	5
right hemisphere of cerebellum	4
cortical plate	4
left testis	4
endothelial cell	4
oocyte	4
type B pancreatic cell	3
right uterine tube	3
substantia nigra pars compacta	2
substantia nigra pars reticulata	2
postcentral gyrus	2
lateral globus pallidus	2
putamen	2
cerebellar hemisphere	2
buccal mucosa cell	2
lower esophagus mucosa	2
monocyte	2
stromal cell of endometrium	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SPR	255	ubiquitous	marker	mucosa of transverse colon, right lobe of liver, right adrenal gland
TACR1	183	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, endocervix, subcutaneous adipose tissue
TH	147	tissue_specific	marker	substantia nigra pars reticulata, substantia nigra pars compacta, male germ line stem cell (sensu Vertebrata) in testis
ACTB	295	ubiquitous	marker	urethra, postcentral gyrus, saphenous vein
ANO3	189	broad	marker	corpus epididymis, lateral globus pallidus, putamen
CAMK2B	233	broad	marker	cerebellar cortex, cerebellar hemisphere, right hemisphere of cerebellum
CASK	284	ubiquitous	marker	buccal mucosa cell, hair follicle, cortical plate
KMT2B	269	ubiquitous	marker	right testis, left testis, lower esophagus mucosa
PANK2	282	ubiquitous	marker	endothelial cell, stromal cell of endometrium, monocyte
CIZ1	281	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, right ovary
GJC2	181	tissue_specific	yes	C1 segment of cervical spinal cord, spinal cord, inferior vagus X ganglion
RHOBTB2	213	ubiquitous	marker	upper lobe of left lung, upper lobe of lung, right frontal lobe
THAP1	260	ubiquitous	yes	secondary oocyte, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
ARFGEF3	223	broad	marker	parotid gland, cerebellar vermis, substantia nigra pars reticulata
SATB2	235	ubiquitous	marker	periodontal ligament, cortical plate, mucosa of sigmoid colon
NTMT1	252	ubiquitous	marker	left testis, right testis, left ventricle myocardium
CHMP1B	282	ubiquitous	marker	gastrocnemius, muscle of leg, type B pancreatic cell
CSTB	300	ubiquitous	marker	lower esophagus mucosa, tongue squamous epithelium, pharyngeal mucosa
CEP104	284	ubiquitous	marker	secondary oocyte, buccal mucosa cell, sperm
PNPLA4	276	ubiquitous	marker	oocyte, hindlimb stylopod muscle, diaphragm
C19orf12	253	ubiquitous	marker	endothelial cell, kidney epithelium, epithelial cell of pancreas
WDR73	275	ubiquitous	marker	right uterine tube, right lobe of thyroid gland, pituitary gland
DCTN1	275	ubiquitous	marker	right frontal lobe, prefrontal cortex, right hemisphere of cerebellum
DRD2	159	broad	yes	putamen, nucleus accumbens, male germ line stem cell (sensu Vertebrata) in testis
TOR1A	274	ubiquitous	marker	stromal cell of endometrium, secondary oocyte, monocyte
AFG3L2	288	ubiquitous	marker	Brodmann (1909) area 23, endothelial cell, jejunal mucosa
C2orf78	7		marker	male germ line stem cell (sensu Vertebrata) in testis, left testis, right testis
FUS	304	ubiquitous	marker	right testis, ventricular zone, right hemisphere of cerebellum
GCH1	275	ubiquitous	marker	secondary oocyte, oocyte, type B pancreatic cell
GNAL	274	broad	marker	lateral globus pallidus, lateral nuclear group of thalamus, middle temporal gyrus

Protein interactions among cohort

Intra-cohort edges: 27.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MECP2	5,688
FUS	5,250
IMPDH2	4,587
MYO5A	4,333
AFG3L2	4,260
CASK	4,223
MRE11	3,932
ATP1A3	3,876
DCTN1	3,654
MT-ND1	3,537

Intra-cohort edges

A	B	Sources
ANO3	ATP1A3	string_interaction
ANO3	CIZ1	string_interaction
ANO3	GNAL	string_interaction
ANO3	THAP1	string_interaction
ANO3	TOR1A	string_interaction
ATP1A3	ATP4A	intact
ATP1A3	THAP1	string_interaction
ATP1A3	TOR1A	string_interaction
C19orf12	PANK2	string_interaction
CAMK2B	GRIA3	string_interaction
CIZ1	GNAL	string_interaction
CIZ1	THAP1	string_interaction
CIZ1	TOR1A	string_interaction
DCTN1	SETX	string_interaction
DRD2	TH	string_interaction
DRD2	THAP1	string_interaction
FUS	SETX	string_interaction
GCH1	SPR	string_interaction
GCH1	TH	string_interaction
GCH1	THAP1	string_interaction
GCH1	TOR1A	string_interaction
GNAL	THAP1	string_interaction
GNAL	TOR1A	string_interaction
KMT2B	THAP1	string_interaction
MT-ND1	MT-ND6	string_interaction
SPR	TH	string_interaction
THAP1	TOR1A	string_interaction

Structural data

PDB: 34 · AlphaFold-only: 11 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GNB1	P62873	1,262
ACTB	P60709	88
IMPDH2	P12268	25
FUS	P35637	23
CASK	O14936	22
NPC1	O15118	20
NTMT1	Q9BV86	18
TACR1	P25103	15
SPR	P35270	14
DCTN1	Q14203	13
CHMP1B	Q7LBR1	11
DRD2	P14416	11
GCH1	P30793	11
GNAL	P38405	10
MRE11	P49959	10
MECP2	P51608	9
TH	P07101	7
MT-ND4	C0HME5	7
MYO5A	Q9Y4I1	7
MT-ND1	P03886	5
MT-ND6	P03923	5
ATP1A3	P13637	5
CAMK2B	Q13554	4
KMT2B	Q9UMN6	4
THAP1	Q9NVV9	3
SATB2	Q9UPW6	3
CSTB	P04080	3
TOR1A	O14656	3
CEP104	O60308	2
AFG3L2	Q9Y4W6	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PNPLA4	P41247	94.38
ATP4A	P20648	88.70
GRIA3	P42263	83.98
RHOBTB2	Q9BYZ6	81.89
ANO3	Q9BYT9	76.30
GJC2	Q5T442	68.50
PCDH12	Q9NPG4	66.22
ARFGEF3	Q5TH69	65.15
C19orf12	Q9NSK7	59.50
SETX	Q7Z333	52.93
C2orf78	A6NCI8	42.92

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 312. Enrichment computed across 45 evidence-associated genes (34 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 34 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation	2	67.2×	0.059	SPR, GCH1
Ion transport by P-type ATPases	3	18.3×	0.059	CAMK2B, ATP1A3, ATP4A
Ion channel transport	4	11.3×	0.059	ANO3, CAMK2B, ATP1A3, ATP4A
Complex I biogenesis	3	14.6×	0.086	MT-ND1, MT-ND4, MT-ND6
Trafficking of AMPA receptors	2	32.0×	0.091	CAMK2B, GRIA3
Unblocking of NMDA receptors, glutamate binding and activation	2	32.0×	0.091	CAMK2B, GRIA3
Loss of MECP2 binding ability to 5hmC-DNA	1	335.9×	0.103	MECP2
Signaling by RAS mutants	2	24.9×	0.103	ACTB, CAMK2B
Regulation of MECP2 expression and activity	2	21.7×	0.103	CAMK2B, MECP2
Parasite infection	2	20.4×	0.103	ACTB, MYO5A
Leishmania phagocytosis	2	20.4×	0.103	ACTB, MYO5A
Mitochondrial protein degradation	3	10.1×	0.103	AFG3L2, MT-ND1, MT-ND6
Mitochondrial translation termination	3	9.7×	0.103	MT-ND1, MT-ND4, MT-ND6
Nucleotide biosynthesis	1	167.9×	0.107	IMPDH2
Transcriptional Regulation by MECP2	2	18.7×	0.107	CAMK2B, MECP2
Fcgamma receptor (FCGR) dependent phagocytosis	2	16.4×	0.107	ACTB, MYO5A
Signaling by RAF1 mutants	2	16.4×	0.107	ACTB, CAMK2B
Regulation of MITF-M-dependent genes involved in pigmentation	2	15.6×	0.107	ACTB, MYO5A
Signaling by moderate kinase activity BRAF mutants	2	14.9×	0.107	ACTB, CAMK2B
Paradoxical activation of RAF signaling by kinase inactive BRAF	2	14.9×	0.107	ACTB, CAMK2B
Assembly and cell surface presentation of NMDA receptors	2	14.9×	0.107	CAMK2B, CASK
Signaling downstream of RAS mutants	2	14.9×	0.107	ACTB, CAMK2B
Respiratory electron transport	3	8.4×	0.107	MT-ND1, MT-ND4, MT-ND6
Oncogenic MAPK signaling	2	14.6×	0.107	ACTB, CAMK2B
MECP2 regulates transcription of genes involved in GABA signaling	1	112.0×	0.111	MECP2
Catecholamine biosynthesis	1	84.0×	0.113	TH
Activation of AMPA receptors	1	84.0×	0.113	GRIA3
Loss of phosphorylation of MECP2 at T308	1	84.0×	0.113	MECP2
Loss of MECP2 binding ability to 5mC-DNA	1	84.0×	0.113	MECP2
Ion homeostasis	2	12.0×	0.113	CAMK2B, ATP1A3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 43 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
nervous system process involved in regulation of systemic arterial blood pressure	2	261.3×	0.006	DRD2, MECP2
regulation of synapse structural plasticity	2	195.9×	0.006	CAMK2B, DRD2
aerobic respiration	4	23.1×	0.006	PANK2, MT-ND1, MT-ND4, MT-ND6
tetrahydrobiopterin biosynthetic process	2	112.0×	0.008	SPR, GCH1
regulation of dopamine uptake involved in synaptic transmission	2	112.0×	0.008	DRD2, TOR1A
hyaloid vascular plexus regression	2	112.0×	0.008	TH, DRD2
long-term memory	3	29.4×	0.008	TACR1, DRD2, MECP2
response to nicotine	3	29.4×	0.008	TACR1, DRD2, MT-ND4
mitochondrial respiratory chain complex I assembly	3	28.7×	0.008	MT-ND1, MT-ND4, MT-ND6
response to hypoxia	5	11.1×	0.008	TH, DRD2, MECP2, MT-ND1, MT-ND4
positive regulation of microtubule nucleation	2	98.0×	0.008	DCTN1, MECP2
dopamine biosynthetic process	2	87.1×	0.009	TH, GCH1
mitochondrial electron transport, NADH to ubiquinone	3	25.0×	0.009	MT-ND1, MT-ND4, MT-ND6
adenylate cyclase-activating dopamine receptor signaling pathway	2	71.3×	0.013	GNAL, GNB1
long-term synaptic potentiation	3	19.6×	0.016	CAMK2B, GRIA3, MECP2
proton motive force-driven mitochondrial ATP synthesis	3	18.4×	0.018	MT-ND1, MT-ND4, MT-ND6
autophagy	4	10.2×	0.018	CHMP1B, C19orf12, DRD2, NPC1
neuron projection maintenance	2	52.2×	0.019	DCTN1, ATP1A3
sodium ion export across plasma membrane	2	49.0×	0.019	ATP1A3, ATP4A
cellular response to steroid hormone stimulus	2	49.0×	0.019	NPC1, ATP1A3
intracellular potassium ion homeostasis	2	46.1×	0.019	ATP1A3, ATP4A
regulation of long-term neuronal synaptic plasticity	2	46.1×	0.019	CAMK2B, DRD2
mitochondrial calcium ion homeostasis	2	46.1×	0.019	C19orf12, AFG3L2
dopamine biosynthetic process from tyrosine	1	391.9×	0.029	TH
N-terminal peptidyl-glycine methylation	1	391.9×	0.029	NTMT1
N-terminal peptidyl-proline dimethylation	1	391.9×	0.029	NTMT1
N-terminal peptidyl-serine dimethylation	1	391.9×	0.029	NTMT1
N-terminal peptidyl-serine trimethylation	1	391.9×	0.029	NTMT1
negative regulation of circadian sleep/wake cycle, sleep	1	391.9×	0.029	DRD2
pteridine-containing compound biosynthetic process	1	391.9×	0.029	GCH1

Therapeutics

Drugs indicated for this disease

0 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Incobotulinumtoxina	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Amlodipine, Mexiletine, Trihexyphenidyl.

Drug target analysis

Approved (phase 4): 9 · Phase ≥3: 10 · Phased (≥1): 12 · Undrugged: 33

Druggability breadth: 26 of 45 evidence-associated genes (58%) 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
TACR1	CLOTRIMAZOLE
CAMK2B	FEDRATINIB
CASK	FEDRATINIB
DRD2	CABERGOLINE
GRIA3	PERAMPANEL
IMPDH2	MYCOPHENOLIC ACID
NPC1	NABUMETONE
ATP1A3	OMEPRAZOLE
ATP4A	PANTOPRAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DRD2	298	4
NPC1	90	4
TACR1	42	4
CAMK2B	25	4
CASK	9	4
GRIA3	7	4
ATP1A3	5	4
ATP4A	5	4
IMPDH2	2	4
ACTB	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CLOTRIMAZOLE	4	DRD2, TACR1
ARIPIPRAZOLE	4	DRD2, TACR1
AMOXAPINE	4	DRD2, TACR1
THIOTHIXENE	4	DRD2, TACR1
FIDAXOMICIN	4	TACR1
APREPITANT	4	TACR1
CYCLOSPORINE	4	NPC1, TACR1
RITONAVIR	4	TACR1
TERFENADINE	4	DRD2, NPC1, TACR1
NETUPITANT	4	TACR1
NILOTINIB	4	TACR1
BOSUTINIB	4	CASK, DRD2, TACR1
ASTEMIZOLE	4	DRD2, TACR1
ROLAPITANT	4	TACR1
LANSOPRAZOLE	4	ATP1A3, ATP4A, NPC1, TACR1
PAROXETINE	4	NPC1, TACR1
DEXTROMETHORPHAN	4	TACR1
HALOPERIDOL	4	DRD2, TACR1
ACLIDINIUM BROMIDE	4	TACR1
TRAZODONE	4	DRD2, TACR1
NEFAZODONE	4	DRD2, TACR1
ITRACONAZOLE	4	TACR1
DOXAZOSIN	4	TACR1
CARVEDILOL	4	DRD2, TACR1
ECONAZOLE	4	DRD2, TACR1
TAMOXIFEN	4	DRD2, NPC1, TACR1
MICONAZOLE	4	DRD2, TACR1
FEDRATINIB	4	CAMK2B, CASK
SORAFENIB	4	CAMK2B
RUXOLITINIB	4	CAMK2B, CASK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 10.

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

Symbol	Assays	Type breakdown
DRD2	2,636	Binding:2064, Functional:517, ADMET:54, Unclassified:1
TACR1	620	Binding:506, Functional:111, ADMET:3
CAMK2B	314	Binding:313, Functional:1
GRIA3	126	Binding:113, Functional:13
NTMT1	119	Binding:119
IMPDH2	111	Binding:104, Functional:6, ADMET:1
CASK	92	Binding:92
ATP1A3	45	Binding:45
MRE11	36	Binding:36
ACTB	21	Binding:21
NPC1	18	Binding:13, Functional:5
ATP4A	17	Binding:13, Functional:4
KMT2B	15	Binding:15
GNB1	12	Binding:12
SPR	10	Binding:10
TH	8	Binding:8
FUS	7	Binding:7
SATB2	6	Binding:6
MT-ND1	5	Binding:5
MT-ND6	4	Binding:4
AFG3L2	3	Binding:3
PANK2	1	Binding:1
CSTB	1	Binding:1
DCTN1	1	Binding:1
MECP2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SPR	1.1.1.153	sepiapterin reductase (L-erythro-7,8-dihydrobiopterin-forming)
TH	1.14.16.2	tyrosine 3-monooxygenase
CAMK2B	2.7.11.17	Ca2+/calmodulin-dependent protein kinase
CASK	2.7.11.1, 2.7.4.8	non-specific serine/threonine protein kinase, guanylate kinase
PANK2	2.7.1.33	pantothenate kinase
NTMT1	2.1.1.244	protein N-terminal methyltransferase
AFG3L2	3.4.24.B18
GCH1	3.5.4.16	GTP cyclohydrolase I
IMPDH2	1.1.1.205	IMP dehydrogenase
ATP4A	7.2.2.19	H+/K+-exchanging ATPase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TACR1	620
CAMK2B	314
NTMT1	119
DRD2	2,636
GRIA3	126
IMPDH2	111

Pharmacogenomics

Cohort genes with a PharmGKB record: 45; with CPIC/DPWG dosing guidelines: 0.

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

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)
CLOTRIMAZOLE	4	DRD2, TACR1
ARIPIPRAZOLE	4	DRD2, TACR1
AMOXAPINE	4	DRD2, TACR1
THIOTHIXENE	4	DRD2, TACR1
FIDAXOMICIN	4	TACR1
APREPITANT	4	TACR1
CYCLOSPORINE	4	NPC1, TACR1
RITONAVIR	4	TACR1
TERFENADINE	4	DRD2, NPC1, TACR1
NETUPITANT	4	TACR1
NILOTINIB	4	TACR1
BOSUTINIB	4	CASK, DRD2, TACR1
ASTEMIZOLE	4	DRD2, TACR1
ROLAPITANT	4	TACR1
LANSOPRAZOLE	4	ATP1A3, ATP4A, NPC1, TACR1
PAROXETINE	4	NPC1, TACR1
DEXTROMETHORPHAN	4	TACR1
HALOPERIDOL	4	DRD2, TACR1
ACLIDINIUM BROMIDE	4	TACR1
TRAZODONE	4	DRD2, TACR1
NEFAZODONE	4	DRD2, TACR1
ITRACONAZOLE	4	TACR1
DOXAZOSIN	4	TACR1
CARVEDILOL	4	DRD2, TACR1
ECONAZOLE	4	DRD2, TACR1
TAMOXIFEN	4	DRD2, NPC1, TACR1
MICONAZOLE	4	DRD2, TACR1
FEDRATINIB	4	CAMK2B, CASK
SORAFENIB	4	CAMK2B
RUXOLITINIB	4	CAMK2B, CASK

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	9	TACR1, CAMK2B, CASK, DRD2, GRIA3, IMPDH2, NPC1, ATP1A3, ATP4A
B	Phased (≥1) drug, not yet approved	3	ACTB, NTMT1, GNB1
C	Druggable family + PDB, no drug	5	SPR, TH, PANK2, AFG3L2, GCH1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	28	ANO3, KMT2B, CIZ1, GJC2, RHOBTB2, THAP1, ARFGEF3, SATB2, CHMP1B, CSTB (+18 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SPR	10	—
TH	8	—
ANO3	0	—
KMT2B	15	—
PANK2	1	—
CIZ1	0	—
GJC2	0	—
RHOBTB2	0	—
THAP1	0	—
ARFGEF3	0	—
SATB2	6	—
CHMP1B	0	—
CSTB	1	—
CEP104	0	—
PNPLA4	0	—
C19orf12	0	—
WDR73	0	—
DCTN1	1	—
TOR1A	0	—
AFG3L2	3	—
C2orf78	0	—
FUS	7	—
GCH1	0	—
GNAL	0	—
SETX	0	—
ARF3	0	—
MECP2	1	—
MRE11	36	—
MT-ND1	5	—
MT-ND4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 169.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	140
PHASE2	11
PHASE1	5
PHASE4	4
PHASE2/PHASE3	4
PHASE3	2
PHASE1/PHASE2	2
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00142259	PHASE4	UNKNOWN	Efficacy and Safety of DBS of the GPi in Patients With Primary Generalized and Segmental Dystonia
NCT00950196	PHASE4	COMPLETED	Amantadine for Improving Neurologic Symptoms in Ataxia-Telangiectasia
NCT00998660	PHASE4	COMPLETED	RECHARGE Sub-Study to the Implantable Systems Performance Registry (ISPR)
NCT02263417	PHASE4	COMPLETED	A Randomized Controlled Trail Comparing Subthalamic and Pallidal Deep Brain Stimulation for Dystonia
NCT00004421	PHASE2/PHASE3	COMPLETED	Deep Brain Stimulation in Treating Patients With Dystonia
NCT00169403	PHASE3	UNKNOWN	Pallidal Stimulation in Patients With Idiopathic Generalised Dystonia
NCT00272246	PHASE2/PHASE3	UNKNOWN	Bilateral Internal Pallidum Stimulation in Primary Generalized Dystonia
NCT00608231	PHASE2/PHASE3	WITHDRAWN	Dexmedetomidine Effects on Microelectrode Recording in Deep Brain Stimulation
NCT03232320	PHASE3	COMPLETED	Meditoxin® Treatment in Patients With Cervical Dystonia
NCT04277247	PHASE2/PHASE3	UNKNOWN	Botulinum Toxin Type A for Foot Dystonia-associated Pain in Parkinson’s Disease
NCT02911103	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Deep Brain Stimulation Surgery for Focal Hand Dystonia
NCT07304089	PHASE2	RECRUITING	A Study to Evaluate the Efficacy, Safety, and Tolerability of VIM0423 in Individuals With Isolated Dystonia
NCT00001784	PHASE2	COMPLETED	Mexiletine for the Treatment of Focal Dystonia
NCT00105430	PHASE2	COMPLETED	Deep Brain Stimulation for Cervical Dystonia
NCT00106782	PHASE2	COMPLETED	Transcranial Electrical Polarization to Treat Focal Hand Dystonia
NCT00122044	PHASE2	COMPLETED	Childhood Hypertonia of Central Origin: A Trial of Anticholinergic Treatment Effects
NCT00169338	PHASE2	COMPLETED	Pallidal Stimulation in Patients With Post-anoxic and Idiopathic Dystonia
NCT00331669	PHASE2	UNKNOWN	Efficacy and Safety of Deep Brain Stimulation (DBS) of the Pallidal (GPi) in Patients With Tardive Dystonia
NCT02015039	PHASE1/PHASE2	COMPLETED	Pilot Trial of Botulinum Toxin and Occupational Therapy for Writer’s Cramp
NCT02107261	PHASE2	COMPLETED	Incobotulinum Toxin A (Xeomin®) As A Treatment For Focal Task-Specific Dystonia Of The Musician’s Hand
NCT02470325	PHASE2	UNKNOWN	The Effects of Cannabis on Dystonia and Spasticity on Pediatric Patients
NCT05027997	PHASE2	COMPLETED	Exploratory Study of Dipraglurant (ADX48621) for the Treatment of Patients With Blepharospasm
NCT06412653	PHASE2	COMPLETED	Prospective Pilot Trial to Address Feasibility and Safety of Oral Zinc in GNAO1 Associated Disorders
NCT06554288	PHASE1	RECRUITING	Pharmacogenomic Contributions to Trihexyphenidyl Biotransformation and Response in Children With Dystonic Cerebral Palsy
NCT01433757	PHASE1	COMPLETED	Ampicillin for DYT-1 Dystonia Motor Symptoms
NCT01698450	PHASE1	COMPLETED	Magnetic Resonance (MR) Guided Functional Ultrasound-Neurosurgery for Movement Disorders
NCT02982304	PHASE1	UNKNOWN	Multi-Target Pallidal and Thalamic Deep Brain Stimulation for Hemi-Dystonia
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT04727177	EARLY_PHASE1	UNKNOWN	Precision-targeted Transcranial Magnetic Stimulation in the Treatment of Primary Dystonia
NCT00575081	Not specified	RECRUITING	Physiological Brain Atlas Development
NCT00682513	Not specified	ACTIVE_NOT_RECRUITING	Studies of the Variable Phenotypic Presentations of Rapid-Onset Dystonia Parkinsonism and Other Movement Disorders
NCT01581580	Not specified	RECRUITING	Deep Brain Stimulation Surgery for Movement Disorders
NCT02252380	Not specified	ACTIVE_NOT_RECRUITING	ExAblate Transcranial MRgFUS for the Management of Treatment-Refractory Movement Disorders
NCT02320266	Not specified	ENROLLING_BY_INVITATION	Sensory Gating Measured With Microelectrode Recording (MER) During Deep Brain Stimulation (DBS) Surgery
NCT02553525	Not specified	ENROLLING_BY_INVITATION	Effects of Stimulation Patterns of Deep Brain Stimulation
NCT02686125	Not specified	RECRUITING	Vercise™ DBS Dystonia Prospective Study
NCT03428009	Not specified	RECRUITING	Dystonia Genotype-Phenotype Correlation
NCT03582891	Not specified	ACTIVE_NOT_RECRUITING	The Motor Network in Parkinson’s Disease and Dystonia: Mechanisms of Therapy
NCT03664609	Not specified	RECRUITING	Deep Brain Stimulation (DBS) Retrospective Outcomes Study
NCT03992625	Not specified	RECRUITING	Clinical Outcomes for Deep Brain Stimulation

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
TRIHEXYPHENIDYL	4	2
AMANTADINE	4	1
AMPICILLIN	4	1
MEXILETINE	4	1
SODIUM CHLORIDE	4	1
ZINC ACETATE	4	1
DIPRAGLURANT	2	1
CHEMBL46909	0	1