Cerebellar ataxia

Summary

Cerebellar ataxia (MONDO:0000437) is a disease caused by variants in NPTX1 and PRDX3, with 71 cohort genes and 146 clinical trials. The dominant Reactome pathway is Regulation of insulin secretion (4 cohort genes). Top therapeutic interventions include fondaparinux sodium, riluzole, and amantadine.

At a glance

• Causal genes: NPTX1 (GenCC Strong), PRDX3 (GenCC Strong)
• Cohort genes: 71
• ClinVar variants: 100
• Clinical trials: 146

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cerebellar ataxia
Mondo ID	MONDO:0000437
MeSH	D002524
Orphanet	102002
DOID	DOID:0050753
NCIT	C82341
SNOMED CT	85102008
UMLS	C0007758
MedGen	849
GARD	0019816
Is cancer (heuristic)	no

Also known as: ataxia · ataxia syndrome · ataxia, cerebellar · ataxias, cerebellar · cerebellar ataxias · cerebellar dysmetria · cerebellar dysmetrias · spinocerebellar ataxia · spinocerebellar degeneration

Data availability: 100 ClinVar variants · 4 GenCC gene-disease records · 45 cell lines.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › movement disorder › cerebellar ataxia

Related subtypes (53): chronic tic disorder, choreatic disease, extrapyramidal and movement disease, benign shuddering attacks, transient tic disorder, essential tremor, lingual-facial-buccal dyskinesia, kuru, inherited Creutzfeldt-Jakob disease, Tourette syndrome, clonic hemifacial spasm, Huntington disease, multiple system atrophy, spinal muscular atrophy-progressive myoclonic epilepsy syndrome, benign paroxysmal tonic upgaze of childhood with ataxia, hereditary geniospasm, tremor-nystagmus-duodenal ulcer syndrome, arthrogryposis, Lafora disease, Unverricht-Lundborg syndrome, neuronal intranuclear inclusion disease, Huntington disease-like 3, brain-lung-thyroid syndrome, myoclonus, familial, proximal myopathy with extrapyramidal signs, progressive myoclonic epilepsy type 7, progressive essential tremor-speech impairment-facial dysmorphism-intellectual disability-abnormal behavior syndrome, progressive non-fluent aphasia, opsoclonus-myoclonus syndrome, isolated facial myokymia, primary orthostatic tremor, familial congenital mirror movements, neuroacanthocytosis, behavioral variant of frontotemporal dementia, frontotemporal dementia with motor neuron disease, hyperekplexia, intellectual disability-hyperkinetic movement-truncal ataxia syndrome, neurodegeneration with brain iron accumulation, Huntington disease-like syndrome due to C9ORF72 expansions, variably protease-sensitive prionopathy, corticobasal syndrome, sensorineural hearing loss-early graying-essential tremor syndrome, progressive supranuclear palsy, Sandifer syndrome, psychogenic movement disorders, epilepsy with myoclonic absences, infantile hypotonia-oculomotor anomalies-hyperkinetic movements-developmental delay syndrome, childhood-onset benign chorea with striatal involvement, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, PRRT2-associated paroxysmal movement disorder, SLC6A3-related dopamine transporter deficiency syndrome, dyskinesia with orofacial involvement, autosomal dominant, complex movement disorder with or without neurodevelopmental features

Subtypes (1): hereditary cerebellar ataxia

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

100 retrieved; paginated sample, class counts are floors:

32 uncertain significance, 29 pathogenic, 15 likely pathogenic, 11 pathogenic/likely pathogenic, 10 conflicting classifications of pathogenicity, 1 benign, 1 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
915836	NM_016035.5(COQ4):c.[577C>T;718C>T]		Pathogenic	criteria provided, single submitter
973107	NM_006796.3(AFG3L2):c.[1385C>T;1858C>A]		Pathogenic	no assertion criteria provided
374194	NM_000051.4(ATM):c.689del (p.Asn230fs)	ATM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
453645	NM_000051.4(ATM):c.6867dup (p.Glu2290Ter)	ATM	Pathogenic	criteria provided, multiple submitters, no conflicts
689374	NM_000051.4(ATM):c.3244_3245insG (p.His1082fs)	ATM	Pathogenic	criteria provided, multiple submitters, no conflicts
560724	NM_001127221.2(CACNA1A):c.5559_5560del (p.Tyr1853_Ser1854delinsTer)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
812756	NM_014704.4(CEP104):c.89del (p.Thr30fs)	CEP104	Pathogenic	no assertion criteria provided
224142	NM_004408.4(DNM1):c.139G>A (p.Val47Met)	CIZ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
183336	NM_020247.5(COQ8A):c.1744dup (p.Ser582fs)	COQ8A	Pathogenic	criteria provided, single submitter
974794	GRCh37/hg19 8p23.3-23.1(chr8:176814-11472913)x1	DEFB103B	Pathogenic	no assertion criteria provided
1710296	NM_175929.3(FGF14):c.208+239747CTT[349]	FGF14	Pathogenic	no assertion criteria provided
1338863	NM_001458.5(FLNC):c.5385dup (p.Gly1796fs)	FLNC-AS1	Pathogenic	criteria provided, single submitter
2446708	NM_001278064.2(GRM1):c.2471C>G (p.Thr824Arg)	GRM1	Pathogenic	no assertion criteria provided
804287	NM_002109.6(HARS1):c.910_912dup (p.Leu305dup)	HARS1	Pathogenic	criteria provided, single submitter
7462	NM_002241.5(KCNJ10):c.194G>C (p.Arg65Pro)	KCNJ10	Pathogenic	no assertion criteria provided
933141	NM_021614.4(KCNN2):c.1436_1439del (p.Leu478_Tyr479insTer)	KCNN2	Pathogenic	criteria provided, single submitter
933149	NM_021614.4(KCNN2):c.1931T>C (p.Leu644Pro)	KCNN2	Pathogenic	criteria provided, single submitter
625205	NM_006612.6(KIF1C):c.1051_1055del (p.Asn351fs)	KIF1C	Pathogenic	criteria provided, single submitter
21522	NM_015166.4(MLC1):c.178-10T>A	LOC125446261	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1172597	NM_001172509.2(SATB2):c.1924C>T (p.Gln642Ter)	LOC126806462	Pathogenic	criteria provided, single submitter
1342852	NM_020871.4(LRCH2):c.772A>G (p.Lys258Glu)	LRCH2	Pathogenic	no assertion criteria provided
214652	NM_014874.4(MFN2):c.314C>T (p.Thr105Met)	MFN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9641	NC_012920.1(MT-ATP6):m.8993T>G	MT-ATP6	Pathogenic	reviewed by expert panel
2431351	NM_001395333.1(MTCL1):c.1129C>T (p.Gln377Ter)	MTCL1	Pathogenic	no assertion criteria provided
2966	NM_000271.5(NPC1):c.3019C>G (p.Pro1007Ala)	NPC1	Pathogenic	criteria provided, multiple submitters, no conflicts
374049	NM_000271.5(NPC1):c.1421C>T (p.Pro474Leu)	NPC1	Pathogenic	criteria provided, multiple submitters, no conflicts
6196	NM_003560.4(PLA2G6):c.1634A>C (p.Lys545Thr)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7706	NM_000303.3(PMM2):c.422G>A (p.Arg141His)	PMM2	Pathogenic	criteria provided, multiple submitters, no conflicts
7723	NM_000303.3(PMM2):c.338C>T (p.Pro113Leu)	PMM2	Pathogenic	criteria provided, multiple submitters, no conflicts
374055	NM_001166114.2(PNPLA6):c.4045C>T (p.Arg1349Trp)	PNPLA6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 141 · 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
NPTX1	Strong	Autosomal dominant	spinocerebellar ataxia 50	3
PRDX3	Strong	Autosomal recessive	spinocerebellar ataxia, autosomal recessive 32	5
TSEN54	Limited	Autosomal dominant	cerebellar ataxia	6
ZNF592	Limited	Autosomal recessive	cerebellar ataxia

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TSEN54	Orphanet:166063	Pontocerebellar hypoplasia type 4
TSEN54	Orphanet:2524	Pontocerebellar hypoplasia type 2
ZNF592	Orphanet:83472	CAMOS syndrome
SCN8A	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
SCN8A	Orphanet:306	Self-limited infantile epilepsy
SCN8A	Orphanet:352582	Familial infantile myoclonic epilepsy
SCN8A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
SLC2A1	Orphanet:168577	Hereditary cryohydrocytosis with reduced stomatin
SLC2A1	Orphanet:1942	Epilepsy with myoclonic-atonic seizures
SLC2A1	Orphanet:2131	Alternating hemiplegia of childhood
SLC2A1	Orphanet:53583	Paroxysmal dystonic choreathetosis with episodic ataxia and spasticity
SLC2A1	Orphanet:71277	Classic glucose transporter type 1 deficiency syndrome
SLC2A1	Orphanet:86911	Epilepsy with myoclonic absences
SLC2A1	Orphanet:98811	Paroxysmal exertion-induced dyskinesia
SPTBN2	Orphanet:352403	Spectrin-associated autosomal recessive cerebellar ataxia
SPTBN2	Orphanet:98766	Spinocerebellar ataxia type 5
STXBP1	Orphanet:495818	9q33.3q34.11 microdeletion syndrome
STXBP1	Orphanet:599373	STXBP1-related encephalopathy
SURF1	Orphanet:391351	SURF1-related Charcot-Marie-Tooth disease type 4
SYNGAP1	Orphanet:1942	Epilepsy with myoclonic-atonic seizures
SYNGAP1	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
SYNGAP1	Orphanet:544254	SYNGAP1-related developmental and epileptic encephalopathy
CACNA1A	Orphanet:2131	Alternating hemiplegia of childhood
CACNA1A	Orphanet:2382	Lennox-Gastaut syndrome
CACNA1A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
CACNA1A	Orphanet:569	Familial or sporadic hemiplegic migraine
CACNA1A	Orphanet:71518	Benign paroxysmal torticollis of infancy
CACNA1A	Orphanet:97	Familial paroxysmal ataxia
CACNA1A	Orphanet:98758	Spinocerebellar ataxia type 6
CACNA1G	Orphanet:458803	Spinocerebellar ataxia type 42
SNX14	Orphanet:397709	Intellectual disability-coarse face-macrocephaly-cerebellar hypotrophy syndrome
NOP56	Orphanet:276198	Spinocerebellar ataxia type 36
PNPLA6	Orphanet:1173	Cerebellar ataxia-hypogonadism syndrome
PNPLA6	Orphanet:1180	Ataxia-hypogonadism-choroidal dystrophy syndrome
PNPLA6	Orphanet:139480	Autosomal recessive spastic paraplegia type 39
PNPLA6	Orphanet:2377	Laurence-Moon syndrome
PNPLA6	Orphanet:3363	Trichomegaly-retina pigmentary degeneration-dwarfism syndrome
CIZ1	Orphanet:420492	Adult-onset cervical dystonia, DYT23 type
COQ8A	Orphanet:139485	Autosomal recessive ataxia due to ubiquinone deficiency
MFN2	Orphanet:2398	Multiple symmetric lipomatosis
MFN2	Orphanet:64751	Hereditary motor and sensory neuropathy type 5
MFN2	Orphanet:90118	Severe early-onset axonal neuropathy due to MFN2 deficiency
MFN2	Orphanet:90120	Hereditary motor and sensory neuropathy type 6
MFN2	Orphanet:99947	Autosomal dominant Charcot-Marie-Tooth disease type 2A2
SYNE1	Orphanet:319332	Autosomal recessive myogenic arthrogryposis multiplex congenita
SYNE1	Orphanet:88644	Autosomal recessive ataxia, Beauce type
SYNE1	Orphanet:98853	Autosomal dominant Emery-Dreifuss muscular dystrophy
TDP2	Orphanet:404493	Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to TUD deficiency
SPART	Orphanet:101000	Autosomal recessive spastic paraplegia type 20
PMPCA	Orphanet:1170	Autosomal recessive cerebelloparenchymal disorder type 3

Cohort genes → proteins

71 cohort genes, 68 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	71

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TSEN54	HGNC:27561	ENSG00000182173	Q7Z6J9	tRNA-splicing endonuclease subunit Sen54	gencc
ZNF592	HGNC:28986	ENSG00000166716	Q92610	Zinc finger protein 592	gencc
NPTX1	HGNC:7952	ENSG00000171246	Q15818	Neuronal pentraxin-1	gencc
PRDX3	HGNC:9354	ENSG00000165672	P30048	Thioredoxin-dependent peroxide reductase, mitochondrial	gencc
SCN8A	HGNC:10596	ENSG00000196876	Q9UQD0	Sodium channel protein type 8 subunit alpha	clinvar
SLC2A1	HGNC:11005	ENSG00000117394	P11166	Solute carrier family 2, facilitated glucose transporter member 1	clinvar
SPTBN2	HGNC:11276	ENSG00000173898	O15020	Spectrin beta chain, non-erythrocytic 2	clinvar
STXBP1	HGNC:11444	ENSG00000136854	P61764	Syntaxin-binding protein 1	clinvar
SURF1	HGNC:11474	ENSG00000148290	Q15526	Surfeit locus protein 1	clinvar
SYNGAP1	HGNC:11497	ENSG00000197283	Q96PV0	Ras/Rap GTPase-activating protein SynGAP	clinvar
CACNA1A	HGNC:1388	ENSG00000141837	O00555	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	clinvar
CACNA1G	HGNC:1394	ENSG00000006283	O43497	Voltage-dependent T-type calcium channel subunit alpha-1G	clinvar
CSMD1	HGNC:14026	ENSG00000183117	Q96PZ7	CUB and sushi domain-containing protein 1	clinvar
JMJD8	HGNC:14148	ENSG00000161999	Q96S16	JmjC domain-containing protein 8	clinvar
GUCD1	HGNC:14237	ENSG00000138867	Q96NT3	Protein GUCD1	clinvar
SNX14	HGNC:14977	ENSG00000135317	Q9Y5W7	Sorting nexin-14	clinvar
NOP56	HGNC:15911	ENSG00000101361	O00567	Nucleolar protein 56	clinvar
PNPLA6	HGNC:16268	ENSG00000032444	Q8IY17	Patatin-like phospholipase domain-containing protein 6	clinvar
CIZ1	HGNC:16744	ENSG00000148337	Q9ULV3	Cip1-interacting zinc finger protein	clinvar
COQ8A	HGNC:16812	ENSG00000163050	Q8NI60	Atypical kinase COQ8A, mitochondrial	clinvar
MFN2	HGNC:16877	ENSG00000116688	O95140	Mitofusin-2	clinvar
SYNE1	HGNC:17089	ENSG00000131018	Q8NF91	Nesprin-1	clinvar
PITRM1	HGNC:17663	ENSG00000107959	Q5JRX3	Presequence protease, mitochondrial	clinvar
TDP2	HGNC:17768	ENSG00000111802	O95551	Tyrosyl-DNA phosphodiesterase 2	clinvar
SPART	HGNC:18514	ENSG00000133104	Q8N0X7	Spartin	clinvar
PMPCA	HGNC:18667	ENSG00000165688	Q10713	Mitochondrial-processing peptidase subunit alpha	clinvar
GBA2	HGNC:18986	ENSG00000070610	Q9HCG7	Non-lysosomal glucosylceramidase	clinvar
CLCN2	HGNC:2020	ENSG00000114859	P51788	Chloride channel protein 2	clinvar
VPS39	HGNC:20593	ENSG00000166887	Q96JC1	Vam6/Vps39-like protein	clinvar
UNC13A	HGNC:23150	ENSG00000130477	Q9UPW8	Protein unc-13 homolog A	clinvar
PTRH2	HGNC:24265	ENSG00000141378	Q9Y3E5	Peptidyl-tRNA hydrolase 2, mitochondrial	clinvar
CSNK1E	HGNC:2453	ENSG00000213923	P49674	Casein kinase I isoform epsilon	clinvar
FZR1	HGNC:24824	ENSG00000105325	Q9UM11	Fizzy-related protein homolog	clinvar
CEP104	HGNC:24866	ENSG00000116198	O60308	Centrosomal protein of 104 kDa	clinvar
WDR81	HGNC:26600	ENSG00000167716	Q562E7	WD repeat-containing protein 81	clinvar
MTCL1	HGNC:29121	ENSG00000168502	Q9Y4B5	Microtubule cross-linking factor 1	clinvar
LRCH2	HGNC:29292	ENSG00000130224	Q5VUJ6	Leucine-rich repeat and calponin homology domain-containing protein 2	clinvar
VAT1L	HGNC:29315	ENSG00000171724	Q9HCJ6	Putative NADPH-dependent quinone oxidoreductase VAT1L	clinvar
DYNC1H1	HGNC:2961	ENSG00000197102	Q14204	Cytoplasmic dynein 1 heavy chain 1	clinvar
DNMT1	HGNC:2976	ENSG00000130816	P26358	DNA (cytosine-5)-methyltransferase 1	clinvar
KIF7	HGNC:30497	ENSG00000166813	Q2M1P5	Kinesin-like protein KIF7	clinvar
SEPSECS	HGNC:30605	ENSG00000109618	Q9HD40	O-phosphoseryl-tRNA(Sec) selenium transferase	clinvar
DEFB103B	HGNC:31702	ENSG00000177243	P81534	Beta-defensin 103	clinvar
FAT2	HGNC:3596	ENSG00000086570	Q9NYQ8	Protocadherin Fat 2	clinvar
FGF14	HGNC:3671	ENSG00000102466	Q92915	Fibroblast growth factor 14	clinvar
GJB1	HGNC:4283	ENSG00000169562	P08034	Gap junction beta-1 protein	clinvar
SETX	HGNC:445	ENSG00000107290	Q7Z333	Helicase senataxin	clinvar
GRM1	HGNC:4593	ENSG00000152822	Q13255	Metabotropic glutamate receptor 1	clinvar
HARS1	HGNC:4816	ENSG00000170445	P12081	Histidine–tRNA ligase, cytoplasmic	clinvar
GACAT2	HGNC:50516	ENSG00000265962		gastric cancer associated transcript 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TSEN54	tRNA-splicing endonuclease subunit Sen54	Non-catalytic subunit of the tRNA-splicing endonuclease complex, a complex responsible for identification and cleavage of the splice sites in pre-tRNA.
ZNF592	Zinc finger protein 592	May be involved in transcriptional regulation.
NPTX1	Neuronal pentraxin-1	May be involved in mediating uptake of synaptic material during synapse remodeling or in mediating the synaptic clustering of AMPA glutamate receptors at a subset of excitatory synapses.
PRDX3	Thioredoxin-dependent peroxide reductase, mitochondrial	Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively.
SCN8A	Sodium channel protein type 8 subunit alpha	Pore-forming subunit of a voltage-gated sodium channel complex assuming opened or closed conformations in response to the voltage difference across membranes and through which sodium ions selectively pass along their electrochemical gradie…
SLC2A1	Solute carrier family 2, facilitated glucose transporter member 1	Facilitative glucose transporter, which is responsible for constitutive or basal glucose uptake.
SPTBN2	Spectrin beta chain, non-erythrocytic 2	Probably plays an important role in neuronal membrane skeleton.
STXBP1	Syntaxin-binding protein 1	Participates in the regulation of synaptic vesicle docking and fusion through interaction with GTP-binding proteins.
SURF1	Surfeit locus protein 1	Component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, that regulates cytochrome c oxidase assembly.
SYNGAP1	Ras/Rap GTPase-activating protein SynGAP	Major constituent of the PSD essential for postsynaptic signaling.
CACNA1A	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene exp…
CACNA1G	Voltage-dependent T-type calcium channel subunit alpha-1G	Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene exp…
CSMD1	CUB and sushi domain-containing protein 1	Potential suppressor of squamous cell carcinomas.
JMJD8	JmjC domain-containing protein 8	Functions as a positive regulator of TNF-induced NF-kappa-B signaling.
SNX14	Sorting nexin-14	Plays a role in maintaining normal neuronal excitability and synaptic transmission.
NOP56	Nucleolar protein 56	Involved in the early to middle stages of 60S ribosomal subunit biogenesis.
PNPLA6	Patatin-like phospholipase domain-containing protein 6	Phospholipase B that deacylates intracellular phosphatidylcholine (PtdCho), generating glycerophosphocholine (GroPtdCho).
CIZ1	Cip1-interacting zinc finger protein	May regulate the subcellular localization of CIP/WAF1.
COQ8A	Atypical kinase COQ8A, mitochondrial	Atypical kinase involved in the biosynthesis of coenzyme Q, also named ubiquinone, an essential lipid-soluble electron transporter for aerobic cellular respiration.
MFN2	Mitofusin-2	Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion.
SYNE1	Nesprin-1	Multi-isomeric modular protein which forms a linking network between organelles and the actin cytoskeleton to maintain the subcellular spatial organization.
PITRM1	Presequence protease, mitochondrial	Metalloendopeptidase of the mitochondrial matrix that functions in peptide cleavage and degradation rather than in protein processing.
TDP2	Tyrosyl-DNA phosphodiesterase 2	DNA repair enzyme that can remove a variety of covalent adducts from DNA through hydrolysis of a 5’-phosphodiester bond, giving rise to DNA with a free 5’ phosphate.
SPART	Spartin	Lipophagy receptor that plays an important role in lipid droplet (LD) turnover in motor neurons.
PMPCA	Mitochondrial-processing peptidase subunit alpha	Substrate recognition and binding subunit of the essential mitochondrial processing protease (MPP), which cleaves the mitochondrial sequence off newly imported precursors proteins.
GBA2	Non-lysosomal glucosylceramidase	Non-lysosomal glucosylceramidase that catalyzes the hydrolysis of glucosylceramides/GlcCers (such as beta-D-glucosyl-(1<->1’)-N-acylsphing-4-enine) to free glucose and ceramides (such as N-acylsphing-4-enine).
CLCN2	Chloride channel protein 2	Voltage-gated and osmosensitive chloride channel.
VPS39	Vam6/Vps39-like protein	Regulator of TGF-beta/activin signaling, inhibiting SMAD3- and activating SMAD2-dependent transcription.
UNC13A	Protein unc-13 homolog A	Plays a role in vesicle maturation during exocytosis as a target of the diacylglycerol second messenger pathway.
PTRH2	Peptidyl-tRNA hydrolase 2, mitochondrial	Peptidyl-tRNA hydrolase which releases tRNAs from the ribosome during protein synthesis.
CSNK1E	Casein kinase I isoform epsilon	Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates.
FZR1	Fizzy-related protein homolog	Substrate-specific adapter for the anaphase promoting complex/cyclosome (APC/C) E3 ubiquitin-protein ligase complex.
CEP104	Centrosomal protein of 104 kDa	Required for ciliogenesis and for structural integrity at the ciliary tip.
WDR81	WD repeat-containing protein 81	Functions as a negative regulator of the PI3 kinase/PI3K activity associated with endosomal membranes via BECN1, a core subunit of the PI3K complex.
MTCL1	Microtubule cross-linking factor 1	Microtubule-associated factor involved in the late phase of epithelial polarization and microtubule dynamics regulation.
LRCH2	Leucine-rich repeat and calponin homology domain-containing protein 2	May play a role in the organization of the cytoskeleton.
VAT1L	Putative NADPH-dependent quinone oxidoreductase VAT1L	Putative NADPH-dependent quinone oxidoreductase.
DYNC1H1	Cytoplasmic dynein 1 heavy chain 1	Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules.
DNMT1	DNA (cytosine-5)-methyltransferase 1	DNA methyltransferase that methylates CpG residues.
KIF7	Kinesin-like protein KIF7	Essential for hedgehog signaling regulation: acts both as a negative and positive regulator of sonic hedgehog (Shh) and Indian hedgehog (Ihh) pathways, acting downstream of SMO, through both SUFU-dependent and -independent mechanisms.
SEPSECS	O-phosphoseryl-tRNA(Sec) selenium transferase	Converts O-phosphoseryl-tRNA(Sec) to selenocysteinyl-tRNA(Sec) required for selenoprotein biosynthesis.
DEFB103B	Beta-defensin 103	Exhibits antimicrobial activity against Gram-positive bacteria S.aureus and S.pyogenes, Gram-negative bacteria P.aeruginosa and E.coli and the yeast C.albicans.
FAT2	Protocadherin Fat 2	Involved in the regulation of cell migration.
FGF14	Fibroblast growth factor 14	Probably involved in nervous system development and function.
GJB1	Gap junction beta-1 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.
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.
GRM1	Metabotropic glutamate receptor 1	G-protein coupled receptor for glutamate.
HARS1	Histidine–tRNA ligase, cytoplasmic	Catalyzes the ATP-dependent ligation of histidine to the 3’-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (His-AMP).
ITPR1	Inositol 1,4,5-trisphosphate-gated calcium channel ITPR1	Inositol 1,4,5-trisphosphate-gated calcium channel that, upon inositol 1,4,5-trisphosphate binding, mediates calcium release from the endoplasmic reticulum (ER).
KCNA6	Potassium voltage-gated channel subfamily A member 6	Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes.

Protein-family classification

Druggable: 27 · Difficult: 10 · Unknown: 34 · Druggable fraction: 0.38

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	7	11.0×	4e-05
Kinase	5	1.9×	0.678
Complement	1	3.8×	0.715
Enzyme (other)	8	1.4×	0.715
Phosphatase	1	1.2×	0.902
Transporter	1	1.1×	0.902
Protease	2	1.0×	0.902
Scaffold/PPI	4	1.0×	0.902
Other/Unknown	34	0.9×	0.952
Transcription factor	6	0.7×	0.952
Antibody/Immunoglobulin	1	0.4×	0.952
GPCR	1	0.3×	0.952

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TSEN54	Enzyme (other)	yes	4.6.1.16	tRNA_splic_suSen54_N, tRNA_splic_suSen54
ZNF592	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Znf-C2H2_11
NPTX1	Other/Unknown	no		PTX_dom, ConA-like_dom_sf, Pentaxin_CS
PRDX3	Other/Unknown	no		AhpC/TSA, Thioredoxin_domain, Peroxiredoxin_C
SCN8A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
SLC2A1	Transporter	yes		Glu_transpt_1, Sugar/inositol_transpt, MFS_sugar_transport-like
SPTBN2	Scaffold/PPI	no		Actinin_actin-bd_CS, PH_dom-spectrin-type, CH_dom
STXBP1	Other/Unknown	no		Sec1-like, Sec1-like_dom2, Sec1-like_sf
SURF1	Other/Unknown	no		Surf1/Shy1, Surf1/Surf4
SYNGAP1	Scaffold/PPI	no		C2_dom, PH_domain, RasGAP_dom
CACNA1A	Ion channel	yes		VDCCAlpha1, CACNA1A, Ion_trans_dom
CACNA1G	Ion channel	yes		VDCCAlpha1, VDCC_T_a1, Ion_trans_dom
CSMD1	Complement	yes		Sushi_SCR_CCP_dom, CUB_dom, Sperma_CUB_dom_sf
JMJD8	Other/Unknown	no		JmjC_dom, Cupin_8, JMJD6_ArgDemeth/LysHydrox
GUCD1	Other/Unknown	no		GUCD1
SNX14	Other/Unknown	no		PX_dom, Phox_assoc, Sorting_nexin_C
NOP56	Other/Unknown	no		Nop_dom, NOP58/56_N, NOSIC
PNPLA6	Other/Unknown	no		cNMP-bd_dom, LysoPLipase_patatin_CS, PNPLA_dom
CIZ1	Transcription factor	no		Matrin/U1-C_Znf_C2H2, Matrin/U1-like-C_Znf_C2H2, Znf_C2H2_type
COQ8A	Kinase	yes		ABC1_dom, Kinase-like_dom_sf, ADCK3_dom
MFN2	Other/Unknown	no		Fzo/mitofusin_HR2, Mitofusin_fam, P-loop_NTPase
SYNE1	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, Spectrin_repeat
PITRM1	Protease	yes	3.4.24.56	Peptidase_M16_C, Metalloenz_LuxS/M16, Pept_M16_N
TDP2	Phosphatase	yes		Endo/exonuclease/phosphatase, UBA-like_sf, Endo/exonu/phosph_ase_sf
SPART	Other/Unknown	no		MIT_dom, Senescence/spartin_C, MIT_dom_sf
PMPCA	Protease	yes	3.4.24.64	Pept_M16_Zn_BS, Peptidase_M16_C, Metalloenz_LuxS/M16
GBA2	Enzyme (other)	yes	3.2.1.45	GH116_catalytic, 6-hairpin_glycosidase_sf, 6hp_glycosidase-like_sf
CLCN2	Other/Unknown	no		ClC, Cl-channel-2, Cl-channel_core
VPS39	Transcription factor	no		Clathrin_H-chain/VPS_repeat, CNH_dom, VPS39/TGF_beta_rcpt-assoc_1
UNC13A	Other/Unknown	no		C2_dom, PKC_DAG/PE, MUN_dom
PTRH2	Enzyme (other)	yes	3.1.1.29	PTH2, Pep_tRNA_hydro_II_dom_sf
CSNK1E	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
FZR1	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_CS
CEP104	Transcription factor	no		Galactose-bd-like_sf, ARM-like, ARM-type_fold
WDR81	Kinase	yes		BEACH_dom, WD40_rpt, Kinase-like_dom_sf
MTCL1	Other/Unknown	no		SOGA_CC, SOGA1/2-like_CC, MTCL1-3
LRCH2	Other/Unknown	no		Leu-rich_rpt, CH_dom, Leu-rich_rpt_typical-subtyp
VAT1L	Other/Unknown	no		Quin_OxRdtase/zeta-crystal_CS, GroES-like_sf, ADH-like_N
DYNC1H1	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail
DNMT1	Transcription factor	no	2.1.1.37	BAH_dom, C5_MeTfrase, Znf_CXXC
KIF7	Other/Unknown	no		Kinesin_motor_dom, Kinesin_motor_CS, P-loop_NTPase
SEPSECS	Enzyme (other)	yes	2.9.1.2	SepSecS/SepCysS, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase
DEFB103B	Other/Unknown	no		Defensin_beta-like
FAT2	Other/Unknown	no		EGF, Laminin_G, EGF-like_Ca-bd_dom
FGF14	Other/Unknown	no		Fibroblast_GF_fam, IL1/FGF
GJB1	Other/Unknown	no		Connexin, Connexin32, Connexin_N
SETX	Other/Unknown	no		P-loop_NTPase, DNA2/NAM7_AAA_11, DNA2/NAM7-like_C
GRM1	GPCR	yes		GPCR_3_mtglu_rcpt, GPCR_3, GPCR_3_mGluR1
HARS1	Enzyme (other)	yes	6.1.1.21	WHEP-TRS_dom, Anticodon-bd, HisRS/HisZ
GACAT2	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

62 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)	71
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar hemisphere	11
right hemisphere of cerebellum	11
apex of heart	8
cerebellar cortex	7
middle temporal gyrus	6
calcaneal tendon	6
cortical plate	6
granulocyte	5
right uterine tube	5
adrenal tissue	5
ventricular zone	5
secondary oocyte	5
Brodmann (1909) area 23	4
sural nerve	4
lateral nuclear group of thalamus	4
right lobe of liver	4
right frontal lobe	4
oocyte	4
ganglionic eminence	4
cerebellar vermis	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TSEN54	232	ubiquitous	marker	granulocyte, right uterine tube, cerebellar hemisphere
ZNF592	241	ubiquitous	yes	pancreatic ductal cell, epithelial cell of pancreas, tibialis anterior
NPTX1	210	broad	marker	cerebellar vermis, paraflocculus, middle temporal gyrus
PRDX3	294	ubiquitous	marker	adrenal tissue, right adrenal gland cortex, right adrenal gland
SCN8A	194	ubiquitous	marker	Brodmann (1909) area 23, middle temporal gyrus, postcentral gyrus
SLC2A1	250	ubiquitous	marker	tibial nerve, sural nerve, skin of abdomen
SPTBN2	238	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
STXBP1	287	ubiquitous	marker	middle temporal gyrus, lateral nuclear group of thalamus, Brodmann (1909) area 23
SURF1	183	ubiquitous	marker	apex of heart, body of pancreas, right lobe of liver
SYNGAP1	137	ubiquitous	marker	pituitary gland, right uterine tube, adenohypophysis
CACNA1A	237	broad	marker	cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex
CACNA1G	194	broad	yes	lateral nuclear group of thalamus, right hemisphere of cerebellum, right frontal lobe
CSMD1	179	broad	marker	Brodmann (1909) area 23, middle temporal gyrus, primary visual cortex
JMJD8	222	ubiquitous	marker	apex of heart, thoracic aorta, left uterine tube
GUCD1	255	ubiquitous	marker	apex of heart, oocyte, ileal mucosa
SNX14	255	ubiquitous	marker	left testis, right testis, calcaneal tendon
NOP56	294	ubiquitous	marker	cervix squamous epithelium, granulocyte, right hemisphere of cerebellum
PNPLA6	276	ubiquitous	marker	granulocyte, metanephros cortex, upper lobe of left lung
CIZ1	281	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, right ovary
COQ8A	134	ubiquitous	marker	gastrocnemius, skeletal muscle tissue, hindlimb stylopod muscle
MFN2	297	ubiquitous	marker	apex of heart, heart left ventricle, cardiac ventricle
SYNE1	275	ubiquitous	marker	cerebellar hemisphere, right hemisphere of cerebellum, calcaneal tendon
PITRM1	292	ubiquitous	marker	apex of heart, adrenal tissue, right adrenal gland cortex
TDP2	292	ubiquitous	marker	jejunal mucosa, mucosa of sigmoid colon, colonic mucosa
SPART	286	ubiquitous	marker	calcaneal tendon, adrenal tissue, left ovary
PMPCA	276	ubiquitous	marker	right lobe of liver, adrenal tissue, apex of heart
GBA2	248	ubiquitous	marker	metanephros cortex, right hemisphere of cerebellum, small intestine Peyer’s patch
CLCN2	181	broad	yes	mucosa of transverse colon, tibial nerve, sural nerve
VPS39	287	ubiquitous	marker	right uterine tube, granulocyte, mucosa of stomach
UNC13A	193	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 15.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATM	7,383
DNMT1	7,179
FZR1	5,895
SLC2A1	5,711
NOP56	4,968
PRDX3	4,736
DYNC1H1	4,215
MFN2	3,853
PMPCA	3,679
ITPR1	3,483

Intra-cohort edges

A	B	Sources
ATP6V0A1	SLC2A1	intact
ATP6V0A1	SYNGAP1	intact
COQ8A	PMPCA	biogrid_interaction, intact
FGF14	SCN8A	biogrid_interaction, intact, string_interaction
FGF14	SPTBN2	string_interaction
GBA2	PNPLA6	string_interaction
GRM1	ITPR1	string_interaction
GUCD1	SYNGAP1	intact
KCNA6	SCN8A	string_interaction
MT-ATP6	MT-CO3	string_interaction
PNPLA6	SPART	string_interaction
PRKCG	SPTBN2	string_interaction
SEPSECS	TSEN54	string_interaction
SPTBN2	ZNF592	string_interaction
STXBP1	UNC13A	string_interaction

Structural data

PDB: 47 · AlphaFold-only: 21 · No structure: 3

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DYNC1H1	Q14204	97
DNMT1	P26358	27
NPC1	O15118	20
KCNN2	Q9H2S1	16
GJB1	P08034	15
ATM	Q13315	14
HARS1	P12081	10
MT-ATP6	P00846	10
PITRM1	Q5JRX3	8
CLCN2	P51788	8
GRM1	Q13255	8
SCN8A	Q9UQD0	7
SEPSECS	Q9HD40	7
ATP6V0A1	Q93050	7
PDE1B	Q01064	7
PMM2	O15305	7
FZR1	Q9UM11	6
CAPRIN1	Q14444	6
TSEN54	Q7Z6J9	5
SLC2A1	P11166	5
TDP2	O95551	5
KIF7	Q2M1P5	5
CACNA1A	O00555	4
COQ8A	Q8NI60	4
KCNJ10	P78508	4
SPTBN2	O15020	3
SNX14	Q9Y5W7	3
NOP56	O00567	3
MFN2	O95140	3
SYNE1	Q8NF91	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
JMJD8	Q96S16	91.33
GBA2	Q9HCG7	89.77
PMPCA	Q10713	88.46
POMT1	Q9Y6A1	88.09
GUCD1	Q96NT3	86.92
PLA2G6	O60733	86.16
SURF1	Q15526	82.62
FGF14	Q92915	79.77
KCNA6	P17658	75.42
UNC13A	Q9UPW8	73.58
PEX6	Q13608	69.87
PNPLA6	Q8IY17	69.75
WDR81	Q562E7	69.23
PCDH12	Q9NPG4	66.22
LRCH2	Q5VUJ6	62.83
SYNGAP1	Q96PV0	60.43
ZNF592	Q92610	54.79
SETX	Q7Z333	52.93
MTCL1	Q9Y4B5	51.33
FAT2	Q9NYQ8
ITPR1	Q14643

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 309. Enrichment computed across 71 evidence-associated genes (52 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 52 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of insulin secretion	4	16.9×	0.027	SLC2A1, STXBP1, CACNA1A, ITPR1
Interaction between L1 and Ankyrins	3	21.2×	0.057	SCN8A, SPTBN2, L1CAM
Neuronal System	6	5.1×	0.110	STXBP1, CACNA1A, KCNA6, KCNJ10, KCNN2, PRKCG
cGMP effects	2	27.4×	0.181	ITPR1, PDE1B
Defective PMM2 causes PMM2-CDG	1	219.6×	0.187	PMM2
Defective SLC2A1 causes GLUT1 deficiency syndrome 1 (GLUT1DS1)	1	219.6×	0.187	SLC2A1
Potassium transport channels	1	73.2×	0.187	KCNJ10
Oligomerization of connexins into connexons	1	73.2×	0.187	GJB1
Transport of connexins along the secretory pathway	1	73.2×	0.187	GJB1
Defective POMT2 causes MDDGA2, MDDGB2 and MDDGC2	1	73.2×	0.187	POMT1
Defective POMT1 causes MDDGA1, MDDGB1 and MDDGC1	1	73.2×	0.187	POMT1
Lactose synthesis	1	73.2×	0.187	SLC2A1
Role of phospholipids in phagocytosis	2	17.6×	0.187	ITPR1, PLA2G6
Phase 0 - rapid depolarisation	2	13.3×	0.187	SCN8A, FGF14
G-protein mediated events	2	12.6×	0.187	ITPR1, PRKCG
DAG and IP3 signaling	2	12.2×	0.187	ITPR1, PRKCG
Beta-catenin independent WNT signaling	2	11.3×	0.187	ITPR1, PRKCG
Meiosis	2	11.0×	0.187	SYNE1, ATM
Selective autophagy	2	10.7×	0.187	MFN2, ATM
NCAM signaling for neurite out-growth	2	10.5×	0.187	SPTBN2, CACNA1G
Opioid Signalling	2	10.2×	0.187	ITPR1, PRKCG
PLC beta mediated events	2	10.2×	0.187	ITPR1, PRKCG
Integration of energy metabolism	3	10.1×	0.187	STXBP1, CACNA1A, ITPR1
Potassium Channels	3	7.8×	0.187	KCNA6, KCNJ10, KCNN2
L1CAM interactions	3	6.9×	0.187	SCN8A, SPTBN2, L1CAM
Signaling by WNT	3	6.5×	0.187	CSNK1E, ITPR1, PRKCG
Hemostasis	5	3.5×	0.187	MFN2, ITPR1, KIF1C, L1CAM, PRKCG
Cam-PDE 1 activation	1	54.9×	0.193	PDE1B
DAG1 core M1 glycosylations	1	54.9×	0.193	POMT1
Disinhibition of SNARE formation	1	43.9×	0.205	PRKCG

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 65 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 aldosterone biosynthetic process	1	259.3×	0.086	CLCN2
epigenetic programming of gene expression	1	259.3×	0.086	DNMT1
negative regulation of collateral sprouting in absence of injury	1	259.3×	0.086	SPART
positive regulation of termination of DNA-templated transcription	1	259.3×	0.086	SETX
SA node cell to atrial cardiac muscle cell signaling	1	259.3×	0.086	CACNA1G
AV node cell to bundle of His cell signaling	1	259.3×	0.086	CACNA1G
obsolete positive regulation of vesicle docking	1	259.3×	0.086	STXBP1
regulation of deadenylation-dependent decapping of nuclear-transcribed mRNA	1	259.3×	0.086	CAPRIN1
regulation of pyruvate kinase activity	1	259.3×	0.086	JMJD8
regulation of acrosomal vesicle exocytosis	1	259.3×	0.086	STXBP1
cyclodextrin metabolic process	1	259.3×	0.086	NPC1
conversion of seryl-tRNAsec to selenocys-tRNAsec	1	129.6×	0.086	SEPSECS
histidyl-tRNA aminoacylation	1	129.6×	0.086	HARS1
response to nickel cation	1	129.6×	0.086	CACNA1G
cerebellar Purkinje cell layer morphogenesis	1	129.6×	0.086	SPTBN2
positive regulation of DNA-templated DNA replication initiation	1	129.6×	0.086	CIZ1
glutamate reuptake	1	129.6×	0.086	KCNJ10
cell differentiation involved in salivary gland development	1	129.6×	0.086	CLCN2
obsolete GDP-D-mannose biosynthetic process from fructose-6-phosphate	1	129.6×	0.086	PMM2
establishment of RNA localization to telomere	1	129.6×	0.086	ATM
establishment of protein-containing complex localization to telomere	1	129.6×	0.086	ATM
regulation of membrane depolarization during action potential	1	129.6×	0.086	CLCN2
neuronal dense core vesicle exocytosis	1	129.6×	0.086	UNC13A
positive regulation of glutamate secretion, neurotransmission	1	129.6×	0.086	STXBP1
release of sequestered calcium ion into cytosol by endoplasmic reticulum	1	129.6×	0.086	ITPR1
positive regulation of telomerase catalytic core complex assembly	1	129.6×	0.086	ATM
obsolete negative regulation of vascular associated smooth muscle cell differentiation involved in phenotypic switching	1	129.6×	0.086	DNMT1
tRNA-type intron splice site recognition and cleavage	1	86.4×	0.086	TSEN54
pre-B cell allelic exclusion	1	86.4×	0.086	ATM
glucosylceramide catabolic process	1	86.4×	0.086	GBA2

Therapeutics

Drugs indicated or in trials for this disease

No drug has an approved disease-direct ChEMBL indication for this disease.

4 drugs in clinical trials for this disease (phase 2–3, investigational): efficacy not established — a trial record, not an indication.

Drug	Highest phase
Rovatirelin	Phase 3
Human Immunoglobulin G	Phase 2
Nilotinib	Phase 2
Riluzole	Phase 2

Drug target analysis

Approved (phase 4): 12 · Phase ≥3: 16 · Phased (≥1): 19 · Undrugged: 52

Druggability breadth: 38 of 71 evidence-associated genes (54%) 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
SCN8A	IMIPRAMINE
SLC2A1	EMETINE
CACNA1A	NIMODIPINE
CACNA1G	NIMODIPINE
COQ8A	FEDRATINIB
GBA2	MIGLUSTAT
CSNK1E	AFATINIB
DNMT1	DECITABINE
NPC1	NABUMETONE
ATM	AMIODARONE HYDROCHLORIDE
PDE1B	VARDENAFIL
PRKCG	INGENOL MEBUTATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NPC1	90	4
CSNK1E	37	4
ATM	35	4
SCN8A	25	4
PRKCG	23	4
PDE1B	16	4
COQ8A	14	4
CACNA1G	8	4
SLC2A1	7	4
GBA2	6	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IMIPRAMINE	4	SCN8A
SERTINDOLE	4	SCN8A
PIMOZIDE	4	CACNA1G, SCN8A
NIFEDIPINE	4	SCN8A
DILTIAZEM	4	SCN8A
MIBEFRADIL	4	CACNA1G, NPC1, SCN8A
HALOPERIDOL	4	SCN8A
MEXILETINE	4	SCN8A
AMITRIPTYLINE	4	SCN8A
AMIODARONE	4	SCN8A
CHLORPROMAZINE	4	SCN8A
TETRACAINE	4	SCN8A
EMETINE	4	NPC1, SLC2A1
NIMODIPINE	4	CACNA1A, CACNA1G
TACRINE	4	CACNA1A, CACNA1G
FEDRATINIB	4	COQ8A
VANDETANIB	4	COQ8A, CSNK1E
DASATINIB	4	COQ8A, CSNK1E
ERLOTINIB	4	COQ8A, CSNK1E
MIGLUSTAT	4	GBA2
MIGALASTAT	4	GBA2
AFATINIB	4	CSNK1E
NERATINIB	4	CSNK1E
BOSUTINIB	4	CSNK1E
UMBRALISIB	4	CSNK1E
NINTEDANIB	4	CSNK1E
SUNITINIB	4	CSNK1E
GEFITINIB	4	CSNK1E
DECITABINE	4	DNMT1
AZACITIDINE	4	DNMT1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 16.

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

Symbol	Assays	Type breakdown
PRKCG	627	Binding:611, Functional:15, ADMET:1
CSNK1E	420	Binding:416, ADMET:2, Functional:2
GRM1	284	Functional:177, Binding:107
ATM	240	Binding:233, Functional:5, ADMET:2
DNMT1	233	Binding:229, Functional:3, ADMET:1
PDE1B	192	Binding:180, ADMET:7, Functional:5
SCN8A	173	Binding:148, Functional:16, ADMET:7, Toxicity:2
SLC2A1	158	Binding:130, ADMET:24, Functional:4
CACNA1G	105	Binding:91, Functional:11, ADMET:2, Toxicity:1
COQ8A	93	Binding:93
PLA2G6	47	Binding:47
GBA2	38	Binding:38
TDP2	30	Binding:30
KCNA6	29	Binding:24, Functional:3, Toxicity:1, ADMET:1
KCNN2	22	Binding:22
CACNA1A	19	Binding:18, Functional:1
NPC1	18	Binding:13, Functional:5
FGF14	16	Binding:16
PITRM1	15	Binding:15
ITPR1	13	Binding:12, Functional:1
KCNJ10	10	Binding:10
PRDX3	8	Binding:8
DYNC1H1	7	Binding:7
KIF7	5	Binding:5
HARS1	5	Binding:5
MFN2	3	Binding:3
PMM2	3	Binding:3
FZR1	2	Binding:2
L1CAM	2	Binding:2
CAPRIN1	2	Binding:2
STXBP1	1	Binding:1
NOP56	1	Binding:1
PNPLA6	1	Binding:1
PMPCA	1	Binding:1
CLCN2	1	Binding:1
GJB1	1	Binding:1
MT-ATP6	1	Binding:1
MT-CO3	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TSEN54	4.6.1.16	tRNA-intron lyase
PITRM1	3.4.24.56	insulysin
PMPCA	3.4.24.64	mitochondrial processing peptidase
GBA2	3.2.1.45	glucosylceramidase
PTRH2	3.1.1.29	peptidyl-tRNA hydrolase
CSNK1E	2.7.11.1	non-specific serine/threonine protein kinase
DNMT1	2.1.1.37	DNA (cytosine-5-)-methyltransferase
SEPSECS	2.9.1.2	O-phospho-L-seryl-tRNASec:L-selenocysteinyl-tRNA synthase
HARS1	6.1.1.21	histidine-tRNA ligase
ATM	2.7.11.1	non-specific serine/threonine protein kinase
PDE1B	3.1.4.17	3’,5’-cyclic-nucleotide phosphodiesterase
PEX6	3.6.4.7	peroxisome-assembly ATPase
PLA2G6	3.1.1.4	phospholipase A2
PMM2	5.4.2.8	phosphomannomutase
POMT1	2.4.1.109	dolichyl-phosphate-mannose-protein mannosyltransferase
PRKCG	2.7.11.13	protein kinase C

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN8A	173
SLC2A1	158
CACNA1G	105
CSNK1E	420
DNMT1	233
GRM1	284
ATM	240
PDE1B	192
PRKCG	627

Pharmacogenomics

Cohort genes with a PharmGKB record: 68; 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)
IMIPRAMINE	4	SCN8A
SERTINDOLE	4	SCN8A
PIMOZIDE	4	CACNA1G, SCN8A
NIFEDIPINE	4	SCN8A
DILTIAZEM	4	SCN8A
MIBEFRADIL	4	CACNA1G, NPC1, SCN8A
HALOPERIDOL	4	SCN8A
MEXILETINE	4	SCN8A
AMITRIPTYLINE	4	SCN8A
AMIODARONE	4	SCN8A
CHLORPROMAZINE	4	SCN8A
TETRACAINE	4	SCN8A
EMETINE	4	NPC1, SLC2A1
NIMODIPINE	4	CACNA1A, CACNA1G
TACRINE	4	CACNA1A, CACNA1G
FEDRATINIB	4	COQ8A
VANDETANIB	4	COQ8A, CSNK1E
DASATINIB	4	COQ8A, CSNK1E
ERLOTINIB	4	COQ8A, CSNK1E
MIGLUSTAT	4	GBA2
MIGALASTAT	4	GBA2
AFATINIB	4	CSNK1E
NERATINIB	4	CSNK1E
BOSUTINIB	4	CSNK1E
UMBRALISIB	4	CSNK1E
NINTEDANIB	4	CSNK1E
SUNITINIB	4	CSNK1E
GEFITINIB	4	CSNK1E
DECITABINE	4	DNMT1
AZACITIDINE	4	DNMT1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	12	SCN8A, SLC2A1, CACNA1A, CACNA1G, COQ8A, GBA2, CSNK1E, DNMT1, NPC1, ATM (+2 more)
B	Phased (≥1) drug, not yet approved	7	PITRM1, TDP2, DYNC1H1, GRM1, KCNN2, PLA2G6, PMM2
C	Druggable family + PDB, no drug	7	TSEN54, CSMD1, PTRH2, SEPSECS, HARS1, KCNJ10, L1CAM
D	Druggable family + AlphaFold only, no drug	6	PMPCA, WDR81, ITPR1, KCNA6, PEX6, POMT1
E	Difficult family or no structure, no drug	39	ZNF592, NPTX1, PRDX3, SPTBN2, STXBP1, SURF1, SYNGAP1, JMJD8, GUCD1, SNX14 (+29 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FGF14	16	SCN8A
TSEN54	0	—
ZNF592	0	—
NPTX1	0	—
PRDX3	8	—
SPTBN2	0	—
STXBP1	1	—
SURF1	0	—
SYNGAP1	0	—
CSMD1	0	—
JMJD8	0	—
GUCD1	0	—
SNX14	0	—
NOP56	1	—
PNPLA6	1	—
CIZ1	0	—
MFN2	3	—
SYNE1	0	—
SPART	0	—
PMPCA	1	—
CLCN2	1	—
VPS39	0	—
UNC13A	0	—
PTRH2	0	—
FZR1	2	—
CEP104	0	—
WDR81	0	—
MTCL1	0	—
LRCH2	0	—
VAT1L	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 146.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	116
PHASE2	10
PHASE3	9
PHASE1/PHASE2	4
PHASE1	3
PHASE4	2
PHASE2/PHASE3	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00950196	PHASE4	COMPLETED	Amantadine for Improving Neurologic Symptoms in Ataxia-Telangiectasia
NCT04107740	PHASE4	COMPLETED	C-Trelin Orally Disintegrated(OD) Tablet 5mg in Ataxia Due to Spinocerebellar Degeneration
NCT03408080	PHASE3	ACTIVE_NOT_RECRUITING	Open Pilot Trial of BHV-4157
NCT03701399	PHASE3	ACTIVE_NOT_RECRUITING	Troriluzole in Adult Participants With Spinocerebellar Ataxia
NCT07040137	PHASE3	RECRUITING	Confirmatory Study 3 of KPS-0373 in Patients With Spinocerebellar Degeneration
NCT01104649	PHASE2/PHASE3	COMPLETED	Efficacy of Riluzole in Hereditary Cerebellar Ataxia
NCT01970098	PHASE3	COMPLETED	A Confirmatory Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970111	PHASE3	COMPLETED	An Extension Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970124	PHASE3	COMPLETED	A Long-Term Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970137	PHASE3	COMPLETED	A 24-week Open-label Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT02889302	PHASE3	COMPLETED	An Additional Confirmatory Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT02960893	PHASE2/PHASE3	COMPLETED	Trial in Adult Participants With Spinocerebellar Ataxia (SCA)
NCT03901638	PHASE3	TERMINATED	Tllsh2910 for Ataxia and Gut Microbiota Alteration in Patients of Multiple System Atrophy
NCT06397274	PHASE2	NOT_YET_RECRUITING	Stemchymal® for Polyglutamine Spinocerebellar Ataxia
NCT00034242	PHASE2	COMPLETED	High-Dose Intravenous Immunoglobulin to Treat Cerebellar Degeneration
NCT00202397	PHASE2	COMPLETED	Effect of Riluzole as a Symptomatic Approach in Patients With Chronic Cerebellar Ataxia
NCT00244361	PHASE1/PHASE2	COMPLETED	Effectiveness of Rituximab in Pediatric OMS Patients.
NCT00863538	PHASE2	COMPLETED	Phase II Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01004016	PHASE2	COMPLETED	A Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01350440	PHASE2	COMPLETED	Safety and Efficacy of Intravenous Immune Globulin in Treating Spinocerebellar Ataxia
NCT01649687	PHASE1/PHASE2	COMPLETED	Treatment of Cerebellar Ataxia With Mesenchymal Stem Cells
NCT01958177	PHASE1/PHASE2	UNKNOWN	Clinical Study to Evaluate the Safety and Efficacy BMMNC in Cerebellar Ataxia
NCT02540655	PHASE2	COMPLETED	Efficacy and Safety Study of Stemchymal® in Polyglutamine Spinocerebellar Ataxia
NCT02829268	PHASE1/PHASE2	COMPLETED	A Clinical Trial of Dantrolene Sodium in Pediatric and Adult Patients With Wolfram Syndrome
NCT03932669	PHASE2	COMPLETED	Effect of Nilotinib in Cerebellar Ataxia Patients
NCT04301284	PHASE2	WITHDRAWN	Study of CAD-1883 for Spinocerebellar Ataxia
NCT05125666	PHASE2	UNKNOWN	Efficacy of Dual Task Training on Children With Ataxia After Medulloblastoma Resection
NCT05157802	PHASE1	ACTIVE_NOT_RECRUITING	Promoting Physical Activity Engagement for People With Early-stage Cerebellar Ataxia
NCT00683943	PHASE1	COMPLETED	Lithium Treatment for Patients With Spinocerebellar Ataxia Type I
NCT02287064	PHASE1	UNKNOWN	An Open-label Trial of Intravenous Immune Globulin (IVIG)in Treating Spinocerebellar Ataxias
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT02440763	Not specified	RECRUITING	The EUROSCA Natural History Study
NCT02741440	Not specified	RECRUITING	Natural History of Spinocerebellar Ataxia Type 7 (SCA7)
NCT02841553	Not specified	RECRUITING	Wolfram Syndrome and WFS1-related Disorders International Registry and Clinical Study
NCT03336008	Not specified	RECRUITING	Hong Kong Spinocerebellar Ataxias Registry
NCT03624374	Not specified	RECRUITING	Natural History Study of Leukoencephalopathy With Brainstem and Spinal Cord Involvement and Lactate Elevation (LBSL)
NCT03879018	Not specified	RECRUITING	Retraining Reaching in Cerebellar Ataxia
NCT03881930	Not specified	RECRUITING	Balance Rehabilitation With Modified Visual Input in Patients With Neuropathy
NCT03972202	Not specified	ACTIVE_NOT_RECRUITING	The Role of Cerebellum in Speech
NCT04010214	Not specified	RECRUITING	A Registered Cohort Study on Cerebellar Ataxia in the Organization in South-East China for Cerebellar Ataxia Research (OSCCAR)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
FONDAPARINUX SODIUM	4	2
RILUZOLE	4	2
AMANTADINE	4	1
DANTROLENE SODIUM	4	1
LITHIUM CARBONATE	4	1
RITUXIMAB	4	1
ROVATIRELIN	3	8
TRORILUZOLE	3	5
RIMTUZALCAP	2	1
TALTIRELIN	2	1
CHEMBL4084635	0	2
CHEMBL46909	0	1