Hereditary ataxia

Summary

Hereditary ataxia (MONDO:0100309) is a disease (an umbrella term covering 20 Mondo subtypes) with 67 cohort genes and 12 clinical trials. The dominant Reactome pathway is Neuronal System (10 cohort genes). Top therapeutic interventions include riluzole and troriluzole.

At a glance

• Prevalence: Unknown (Worldwide)
• Umbrella term: 20 Mondo subtypes
• Cohort genes: 67
• ClinVar variants: 83
• Clinical trials: 12

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary ataxia
Mondo ID	MONDO:0100309
EFO	EFO:0009671
MeSH	C531684
Orphanet	183518
DOID	DOID:0050951
ICD-10-CM	G11
ICD-11	442347652
SNOMED CT	763597000
UMLS	C0004138
MedGen	2478
GARD	0020286
Is cancer (heuristic)	no

Also known as: rare hereditary ataxia · SCA

Data availability: 83 ClinVar variants · 1 GenCC gene-disease record · 67 cell lines.

Disease family

An umbrella term covering 20 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › atactic disorder › hereditary ataxia

Related subtypes (3): cerebellar ataxia, acquired ataxia, sensory ataxia

Subtypes (20): ataxia with fasciculations, muscular atrophy-ataxia-retinitis pigmentosa-diabetes mellitus syndrome, myoclonus-cerebellar ataxia-deafness syndrome, cataract-ataxia-deafness syndrome, ataxia-hypogonadism-choroidal dystrophy syndrome, ichthyosis-hepatosplenomegaly-cerebellar degeneration syndrome, Richards-Rundle syndrome, spinocerebellar ataxia-dysmorphism syndrome, ataxia-tapetoretinal degeneration syndrome, hereditary spastic paraplegia 7, autosomal dominant sensory ataxia 1, EAST syndrome, juvenile-onset diabetes mellitus-central and peripheral neurodegeneration syndrome, severe microbrachycephaly-intellectual disability-athetoid cerebral palsy syndrome, hereditary episodic ataxia, spastic ataxia, tremor-ataxia-central hypomyelination syndrome, hereditary cerebellar ataxia, autosomal recessive ataxia due to PEX16 deficiency, autosomal recessive ataxia due to PEX2 deficiency

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

83 retrieved; paginated sample, class counts are floors:

37 uncertain significance, 20 conflicting classifications of pathogenicity, 12 pathogenic/likely pathogenic, 5 likely benign, 3 benign/likely benign, 3 pathogenic, 2 likely pathogenic, 1 benign/likely benign; other

ClinVar	Variant (HGVS)	Gene	Classification	Review
4846767	GRCh38/hg38 4q28.1-28.2(chr4:127842022-127987078)x1	ABHD18	Pathogenic	criteria provided, single submitter
4431	NM_001195248.2(APTX):c.837G>A (p.Trp279Ter)	APTX	Pathogenic	criteria provided, multiple submitters, no conflicts
807379	NM_152296.5(ATP1A3):c.266G>C (p.Gly89Ala)	ATP1A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2735182	NM_000503.6(EYA1):c.1360+5G>A	EYA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13473	NM_004977.3(KCNC3):c.1259G>A (p.Arg420His)	KCNC3	Pathogenic	criteria provided, multiple submitters, no conflicts
995131	NM_001378969.1(KCND3):c.1150G>A (p.Gly384Ser)	KCND3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
589240	NM_001371596.2(MFSD8):c.754+1G>T	MFSD8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1801521	NM_001079668.3(NKX2-1):c.626G>C (p.Arg209Pro)	NKX2-1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
445922	NM_007055.4(POLR3A):c.1909+22G>A	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
617891	NM_007055.4(POLR3A):c.2005C>T (p.Arg669Ter)	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
450250	NM_014363.6(SACS):c.4232T>G (p.Leu1411Ter)	SACS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
504884	NM_014363.6(SACS):c.814C>T (p.Arg272Cys)	SACS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
554798	NM_014363.6(SACS):c.4565_4568del (p.Leu1522fs)	SACS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188276	NM_003119.4(SPG7):c.1672A>T (p.Lys558Ter)	SPG7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6816	NM_003119.4(SPG7):c.233T>A (p.Leu78Ter)	SPG7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1283911	NM_002739.5(PRKCG):c.1926C>G (p.Asn642Lys)	PRKCG	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4074907	NM_002739.5(PRKCG):c.344A>T (p.Asp115Val)	PRKCG	Likely pathogenic	criteria provided, single submitter
2063123	NM_183357.3(ADCY5):c.2890G>T (p.Ala964Ser)	ADCY5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2920140	NM_001099922.3(ALG13):c.362A>G (p.His121Arg)	ALG13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2730551	NM_001374828.1(ARID1B):c.371C>T (p.Ser124Phe)	ARID1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1319271	NM_001220.5(CAMK2B):c.1466C>T (p.Pro489Leu)	CAMK2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2040248	NM_004366.6(CLCN2):c.2425A>G (p.Ile809Val)	CLCN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
586092	NM_000217.3(KCNA1):c.884G>A (p.Arg295His)	KCNA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
840589	NM_004523.4(KIF11):c.749T>C (p.Ile250Thr)	KIF11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
245637	NM_001244008.2(KIF1A):c.3085G>A (p.Val1029Met)	KIF1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
948932	NM_001244008.2(KIF1A):c.4846C>T (p.Arg1616Trp)	KIF1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
92924	NM_001278116.2(L1CAM):c.2302G>A (p.Val768Ile)	L1CAM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
641266	NM_001136472.2(LITAF):c.268C>T (p.Arg90Cys)	LITAF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
696326	NM_014874.4(MFN2):c.1529G>A (p.Arg510Gln)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1049583	NM_001009944.3(PKD1):c.5783C>G (p.Pro1928Arg)	PKD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 158 · 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
PCNA	Supportive	Autosomal recessive	ataxia-telangiectasia-like disorder 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PCNA	Orphanet:438134	PCNA-related progressive neurodegenerative photosensitivity syndrome
SACS	Orphanet:98	Autosomal recessive spastic ataxia of Charlevoix-Saguenay
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
SEC23B	Orphanet:201	Cowden syndrome
SEC23B	Orphanet:98873	Congenital dyserythropoietic anemia type II
SLC6A3	Orphanet:238455	Infantile dystonia-parkinsonism
SPAST	Orphanet:100985	Autosomal dominant spastic paraplegia type 4
SPG7	Orphanet:35689	Primary lateral sclerosis
SPG7	Orphanet:99013	Spastic paraplegia type 7
SPTBN2	Orphanet:352403	Spectrin-associated autosomal recessive cerebellar ataxia
SPTBN2	Orphanet:98766	Spinocerebellar ataxia type 5
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
NKX2-1	Orphanet:1429	Benign hereditary chorea
NKX2-1	Orphanet:146	Differentiated thyroid carcinoma
NKX2-1	Orphanet:209905	Brain-lung-thyroid syndrome
NKX2-1	Orphanet:95713	Athyreosis
TRIO	Orphanet:476126	Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome
USP9X	Orphanet:480880	X-linked female restricted facial dysmorphism-short stature-choanal atresia-intellectual disability
USP9X	Orphanet:777	X-linked non-syndromic intellectual disability
WASF1	Orphanet:528084	Non-specific syndromic intellectual disability
WFS1	Orphanet:3463	Wolfram syndrome
WFS1	Orphanet:411590	Wolfram-like syndrome
WFS1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
WFS1	Orphanet:98991	Early-onset nuclear cataract
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
ANO3	Orphanet:420485	Cranio-cervical dystonia with laryngeal and upper-limb involvement
CIC	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
CAMK2B	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
APTX	Orphanet:1168	Ataxia-oculomotor apraxia type 1
DHX30	Orphanet:647788	Neurodevelopmental delay-intellectual disability-ataxia-feeding difficulty syndrome
LITAF	Orphanet:101083	Charcot-Marie-Tooth disease type 1C
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

Cohort genes → proteins

67 cohort genes, 65 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	67

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PCNA	HGNC:8729	ENSG00000132646	P12004	DNA sliding clamp PCNA	gencc
SACS	HGNC:10519	ENSG00000151835	Q9NZJ4	Sacsin	clinvar
SCN8A	HGNC:10596	ENSG00000196876	Q9UQD0	Sodium channel protein type 8 subunit alpha	clinvar
SEC23B	HGNC:10702	ENSG00000101310	Q15437	Protein transport protein Sec23B	clinvar
SLC6A3	HGNC:11049	ENSG00000142319	Q01959	Sodium-dependent dopamine transporter	clinvar
SPAST	HGNC:11233	ENSG00000021574	Q9UBP0	Spastin	clinvar
SPG7	HGNC:11237	ENSG00000197912	Q9UQ90	Mitochondrial inner membrane m-AAA protease component paraplegin	clinvar
SPTBN2	HGNC:11276	ENSG00000173898	O15020	Spectrin beta chain, non-erythrocytic 2	clinvar
SYNGAP1	HGNC:11497	ENSG00000197283	Q96PV0	Ras/Rap GTPase-activating protein SynGAP	clinvar
NKX2-1	HGNC:11825	ENSG00000136352	P43699	Homeobox protein Nkx-2.1	clinvar
TRIO	HGNC:12303	ENSG00000038382	O75962	Triple functional domain protein	clinvar
USP9X	HGNC:12632	ENSG00000124486	Q93008	Ubiquitin carboxyl-terminal hydrolase 9X	clinvar
WASF1	HGNC:12732	ENSG00000112290	Q92558	Actin-binding protein WASF1	clinvar
WFS1	HGNC:12762	ENSG00000109501	O76024	Wolframin	clinvar
CACNA1A	HGNC:1388	ENSG00000141837	O00555	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	clinvar
ANO3	HGNC:14004	ENSG00000134343	Q9BYT9	Anoctamin-3	clinvar
CIC	HGNC:14214	ENSG00000079432	Q96RK0	Protein capicua homolog	clinvar
CAMK2B	HGNC:1461	ENSG00000058404	Q13554	Calcium/calmodulin-dependent protein kinase type II subunit beta	clinvar
APTX	HGNC:15984	ENSG00000137074	Q7Z2E3	Aprataxin	clinvar
DHX30	HGNC:16716	ENSG00000132153	Q7L2E3	ATP-dependent RNA helicase DHX30	clinvar
LITAF	HGNC:16841	ENSG00000189067	Q99732	Lipopolysaccharide-induced tumor necrosis factor-alpha factor	clinvar
MFN2	HGNC:16877	ENSG00000116688	O95140	Mitofusin-2	clinvar
SYNE1	HGNC:17089	ENSG00000131018	Q8NF91	Nesprin-1	clinvar
ARID1B	HGNC:18040	ENSG00000049618	Q8NFD5	AT-rich interactive domain-containing protein 1B	clinvar
SETD2	HGNC:18420	ENSG00000181555	Q9BYW2	Histone-lysine N-methyltransferase SETD2	clinvar
DEPDC5	HGNC:18423	ENSG00000100150	O75140	GATOR1 complex protein DEPDC5	clinvar
CAMTA1	HGNC:18806	ENSG00000171735	Q9Y6Y1	Calmodulin-binding transcription activator 1	clinvar
TTBK2	HGNC:19141	ENSG00000128881	Q6IQ55	Tau-tubulin kinase 2	clinvar
CLCN2	HGNC:2020	ENSG00000114859	P51788	Chloride channel protein 2	clinvar
COL4A2	HGNC:2203	ENSG00000134871	P08572	Collagen alpha-2(IV) chain	clinvar
PNPT1	HGNC:23166	ENSG00000138035	Q8TCS8	Polyribonucleotide nucleotidyltransferase 1, mitochondrial	clinvar
ADCY5	HGNC:236	ENSG00000173175	O95622	Adenylate cyclase type 5	clinvar
ABHD18	HGNC:26111	ENSG00000164074	Q0P651	Protein ABHD18	clinvar
LINC00964	HGNC:27226	ENSG00000249816		long intergenic non-protein coding RNA 964	clinvar
MFSD8	HGNC:28486	ENSG00000164073	Q8NHS3	Major facilitator superfamily domain-containing protein 8	clinvar
ZSWIM6	HGNC:29316	ENSG00000130449	Q9HCJ5	Zinc finger SWIM domain-containing protein 6	clinvar
ASXL3	HGNC:29357	ENSG00000141431	Q9C0F0	Putative Polycomb group protein ASXL3	clinvar
DNM1L	HGNC:2973	ENSG00000087470	O00429	Dynamin-1-like protein	clinvar
POLR3A	HGNC:30074	ENSG00000148606	O14802	DNA-directed RNA polymerase III subunit RPC1	clinvar
ALG13	HGNC:30881	ENSG00000101901	Q9NP73	UDP-N-acetylglucosamine transferase subunit ALG13	clinvar
SLC6A20	HGNC:30927	ENSG00000163817	Q9NP91	Sodium- and chloride-dependent transporter XTRP3	clinvar
TOR1A	HGNC:3098	ENSG00000136827	O14656	Torsin-1A	clinvar
AGL	HGNC:321	ENSG00000162688	P35573	Glycogen debranching enzyme	clinvar
EYA1	HGNC:3519	ENSG00000104313	Q99502	Protein phosphatase EYA1	clinvar
GFPT1	HGNC:4241	ENSG00000198380	Q06210	Glutamine–fructose-6-phosphate aminotransferase [isomerizing] 1	clinvar
GPC3	HGNC:4451	ENSG00000147257	P51654	Glypican-3	clinvar
HEXA	HGNC:4878	ENSG00000213614	P06865	Beta-hexosaminidase subunit alpha	clinvar
HMBS	HGNC:4982	ENSG00000256269	P08397	Porphobilinogen deaminase	clinvar
SCN1A-AS1	HGNC:54069	ENSG00000236107		SCN1A and SCN9A antisense RNA 1	clinvar
ABCD1	HGNC:61	ENSG00000101986	P33897	ATP-binding cassette sub-family D member 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PCNA	DNA sliding clamp PCNA	Confers DNA tethering and processivity to DNA polymerases and other proteins.
SACS	Sacsin	Co-chaperone which acts as a regulator of the Hsp70 chaperone machinery and may be involved in the processing of other ataxia-linked proteins.
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…
SEC23B	Protein transport protein Sec23B	Component of the coat protein complex II (COPII) which promotes the formation of transport vesicles from the endoplasmic reticulum (ER).
SLC6A3	Sodium-dependent dopamine transporter	Mediates sodium- and chloride-dependent transport of dopamine.
SPAST	Spastin	ATP-dependent microtubule severing protein that specifically recognizes and cuts microtubules that are polyglutamylated.
SPG7	Mitochondrial inner membrane m-AAA protease component paraplegin	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.
SPTBN2	Spectrin beta chain, non-erythrocytic 2	Probably plays an important role in neuronal membrane skeleton.
SYNGAP1	Ras/Rap GTPase-activating protein SynGAP	Major constituent of the PSD essential for postsynaptic signaling.
NKX2-1	Homeobox protein Nkx-2.1	Transcription factor that binds and activates the promoter of thyroid specific genes such as thyroglobulin, thyroperoxidase, and thyrotropin receptor.
TRIO	Triple functional domain protein	Guanine nucleotide exchange factor (GEF) for RHOA and RAC1 GTPases.
USP9X	Ubiquitin carboxyl-terminal hydrolase 9X	Deubiquitinase involved both in the processing of ubiquitin precursors and of ubiquitinated proteins.
WASF1	Actin-binding protein WASF1	Downstream effector molecule involved in the transmission of signals from tyrosine kinase receptors and small GTPases to the actin cytoskeleton.
WFS1	Wolframin	Participates in the regulation of cellular Ca(2+) homeostasis, at least partly, by modulating the filling state of the endoplasmic reticulum Ca(2+) store.
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…
ANO3	Anoctamin-3	Has calcium-dependent phospholipid scramblase activity; scrambles phosphatidylcholine and galactosylceramide.
CIC	Protein capicua homolog	Transcriptional repressor which plays a role in development of the central nervous system (CNS).
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…
APTX	Aprataxin	DNA-binding protein involved in single-strand DNA break repair, double-strand DNA break repair and base excision repair.
DHX30	ATP-dependent RNA helicase DHX30	RNA-dependent helicase.
LITAF	Lipopolysaccharide-induced tumor necrosis factor-alpha factor	Plays a role in endosomal protein trafficking and in targeting proteins for lysosomal degradation.
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.
ARID1B	AT-rich interactive domain-containing protein 1B	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
SETD2	Histone-lysine N-methyltransferase SETD2	Histone methyltransferase that specifically trimethylates ‘Lys-36’ of histone H3 (H3K36me3) using dimethylated ‘Lys-36’ (H3K36me2) as substrate.
DEPDC5	GATOR1 complex protein DEPDC5	As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway.
CAMTA1	Calmodulin-binding transcription activator 1	Transcriptional activator.
TTBK2	Tau-tubulin kinase 2	Serine/threonine kinase that acts as a key regulator of ciliogenesis: controls the initiation of ciliogenesis by binding to the distal end of the basal body and promoting the removal of CCP110, which caps the mother centriole, leading to t…
CLCN2	Chloride channel protein 2	Voltage-gated and osmosensitive chloride channel.
COL4A2	Collagen alpha-2(IV) chain	Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a ‘chicken-wire’ meshwork together with laminins, proteoglycans and entactin/nidogen.
PNPT1	Polyribonucleotide nucleotidyltransferase 1, mitochondrial	RNA-binding protein implicated in numerous RNA metabolic processes.
ADCY5	Adenylate cyclase type 5	Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling.
MFSD8	Major facilitator superfamily domain-containing protein 8	Outward-rectifying chloride channel involved in endolysosomal chloride homeostasis, membrane fusion and function.
ZSWIM6	Zinc finger SWIM domain-containing protein 6	involved in nervous system development, important for striatal morphology and motor regulation.
ASXL3	Putative Polycomb group protein ASXL3	Putative Polycomb group (PcG) protein.
DNM1L	Dynamin-1-like protein	Functions in mitochondrial and peroxisomal division.
POLR3A	DNA-directed RNA polymerase III subunit RPC1	Catalytic core component of RNA polymerase III (Pol III), a DNA-dependent RNA polymerase which synthesizes small non-coding RNAs using the four ribonucleoside triphosphates as substrates.
ALG13	UDP-N-acetylglucosamine transferase subunit ALG13	Catalytic subunit of the UDP-N-acetylglucosamine transferase complex that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation.
SLC6A20	Sodium- and chloride-dependent transporter XTRP3	Mediates the Na(+)- and Cl(-)-dependent uptake of imino acids such as L-proline, N-methyl-L-proline and pipecolate as well as N-methylated amino acids.
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.
AGL	Glycogen debranching enzyme	Multifunctional enzyme acting as 1,4-alpha-D-glucan:1,4-alpha-D-glucan 4-alpha-D-glycosyltransferase and amylo-1,6-glucosidase in glycogen degradation.
EYA1	Protein phosphatase EYA1	Functions both as protein phosphatase and as transcriptional coactivator for SIX1, and probably also for SIX2, SIX4 and SIX5.
GFPT1	Glutamine–fructose-6-phosphate aminotransferase [isomerizing] 1	Rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP) that catalyzes the formation of glucosamine-6-phosphate from fructose-6-phosphate and glutamine, thereby controlling the flux of glucose into this pathway.
GPC3	Glypican-3	Cell surface proteoglycan.
HEXA	Beta-hexosaminidase subunit alpha	Hydrolyzes the non-reducing end N-acetyl-D-hexosamine and/or sulfated N-acetyl-D-hexosamine of glycoconjugates, such as the oligosaccharide moieties from proteins and neutral glycolipids, or from certain mucopolysaccharides.
HMBS	Porphobilinogen deaminase	As part of the heme biosynthetic pathway, catalyzes the sequential polymerization of four molecules of porphobilinogen to form hydroxymethylbilane, also known as preuroporphyrinogen.
ABCD1	ATP-binding cassette sub-family D member 1	ATP-dependent transporter of the ATP-binding cassette (ABC) family involved in the transport of very long chain fatty acid (VLCFA)-CoA from the cytosol to the peroxisome lumen.
ITM2B	Integral membrane protein 2B	Plays a regulatory role in the processing of the amyloid-beta A4 precursor protein (APP) and acts as an inhibitor of the amyloid-beta peptide aggregation and fibrils deposition.
KCNA1	Potassium voltage-gated channel subfamily A member 1	Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain and the central nervous system, but also in the kidney.
KCNC3	Voltage-gated potassium channel KCNC3	Voltage-gated potassium channel that plays an important role in the rapid repolarization of fast-firing brain neurons.

Protein-family classification

Druggable: 28 · Difficult: 11 · Unknown: 28 · Druggable fraction: 0.42

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	11.7×	2e-05
Kinase	6	2.5×	0.151
Transporter	2	2.3×	0.479
Enzyme (other)	8	1.4×	0.479
Antibody/Immunoglobulin	3	1.3×	0.606
Scaffold/PPI	5	1.3×	0.606
Protease	2	1.1×	0.707
Transcription factor	6	0.7×	0.942
Other/Unknown	28	0.8×	0.992

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PCNA	Other/Unknown	no		Pr_cel_nuc_antig, Pr_cel_nuc_antig_N, Pr_cel_nuc_antig_C
SACS	Other/Unknown	no		Ubiquitin-like_dom, DnaJ_domain, HEPN_dom
SCN8A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
SEC23B	Transcription factor	no		Znf_Sec23_Sec24, Sec23/24_trunk_dom, Sec23/24_helical_dom
SLC6A3	Other/Unknown	no		Na/ntran_symport, Na/ntran_symport_dopamine, SNS_sf
SPAST	Enzyme (other)	yes	5.6.1.1	AAA+_ATPase, ATPase_AAA_core, ATPase_AAA_CS
SPG7	Protease	yes	3.4.24.B18	Peptidase_M41, AAA+_ATPase, ATPase_AAA_core
SPTBN2	Scaffold/PPI	no		Actinin_actin-bd_CS, PH_dom-spectrin-type, CH_dom
SYNGAP1	Scaffold/PPI	no		C2_dom, PH_domain, RasGAP_dom
NKX2-1	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
TRIO	Kinase	yes		DH_dom, Prot_kinase_dom, CRAL-TRIO_dom
USP9X	Protease	yes		Peptidase_C19_UCH, ARM-type_fold, USP_CS
WASF1	Other/Unknown	no		WH2_dom, SCAR/WAVE_fam
WFS1	Other/Unknown	no		TPR-like_helical_dom_sf, Wolframin, Wolframin_fam
CACNA1A	Ion channel	yes		VDCCAlpha1, CACNA1A, Ion_trans_dom
ANO3	Other/Unknown	no		Anoctamin, Anoct_dimer, Anoctamin_TM
CIC	Other/Unknown	no		HMG_box_dom, Cic_dom, HMG_box_dom_sf
CAMK2B	Kinase	yes	2.7.11.17	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
APTX	Transcription factor	no	3.1.11.7	SMAD_FHA_dom_sf, HIT-like, Znf_C2H2_type
DHX30	Other/Unknown	no		Helicase_C-like, DNA/RNA_helicase_DEAH_CS, Helicase-assoc_dom
LITAF	Other/Unknown	no		LITAF, LITAF_fam
MFN2	Other/Unknown	no		Fzo/mitofusin_HR2, Mitofusin_fam, P-loop_NTPase
SYNE1	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, Spectrin_repeat
ARID1B	Other/Unknown	no		ARID_dom, BAF250/Osa, BAF250_C
SETD2	Scaffold/PPI	no	2.1.1.359	WW_dom, SET_dom, Post-SET_dom
DEPDC5	Other/Unknown	no		DEP_dom, IML1, WH-like_DNA-bd_sf
CAMTA1	Antibody/Immunoglobulin	yes		IQ_motif_EF-hand-BS, Ankyrin_rpt, IPT_dom
TTBK2	Kinase	yes	2.7.11.26	Prot_kinase_dom, Kinase-like_dom_sf, Protein_kinase_ATP_BS
CLCN2	Other/Unknown	no		ClC, Cl-channel-2, Cl-channel_core
COL4A2	Other/Unknown	no		Collagen_IV_NC, Collagen, CTDL_fold
PNPT1	Scaffold/PPI	no	2.7.7.8	ExoRNase_PH_dom1, S1_domain, KH_dom
ADCY5	Enzyme (other)	yes	4.6.1.1	A/G_cyclase, Adcy_conserved_dom, A/G_cyclase_CS
ABHD18	Other/Unknown	no		ABHD18, AB_hydrolase_fold
LINC00964	Other/Unknown	no
MFSD8	Transporter	yes		MFS, MFS_dom, MFS_trans_sf
ZSWIM6	Transcription factor	no		Znf_SWIM, ZSWIM4-8_C
ASXL3	Other/Unknown	no		Asxl_HARE-HTH, ASX/ASX-like, ASX-like_PHD
DNM1L	Enzyme (other)	yes	3.6.5.5	Dynamin_stalk, Dynamin_GTPase, GED
POLR3A	Other/Unknown	no		RNA_pol_asu, RNA_pol_N, RNA_pol_Rpb1_3
ALG13	Other/Unknown	no		Tudor, OTU_dom, Glyco_trans_28_C
SLC6A20	Other/Unknown	no		Na/ntran_symport, Neutral_aa_SLC6, SNS_sf
TOR1A	Other/Unknown	no		Torsin, Torsin_1/2, P-loop_NTPase
AGL	Enzyme (other)	yes	3.2.1.33	Glycogen_debranch_met, 6-hairpin_glycosidase_sf, AGL/Gdb1
EYA1	Other/Unknown	no		EYA_dom, EYA, EYA_dom_sf
GFPT1	Enzyme (other)	yes	2.6.1.16	SIS_dom, GFAT, GATase_2_dom
GPC3	Other/Unknown	no		Glypican, Glypican_CS
HEXA	Enzyme (other)	yes	3.2.1.169	GH20_cat, GH_hydrolase_sf, GH20
HMBS	Enzyme (other)	yes	2.5.1.61	HemC, Porphobilin_deaminase_N, Porphobilinogen_deaminase_C
SCN1A-AS1	Other/Unknown	no
ABCD1	Transporter	yes	7.6.2.4	ABC_transporter-like_ATP-bd, AAA+_ATPase, FA_transporter

Expression context

Cohort genes with no expression data: 0.

64 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)	67
unknown	0

Top tissues across cohort

Tissue	Cohort genes
secondary oocyte	8
right hemisphere of cerebellum	8
cerebellar hemisphere	7
Brodmann (1909) area 23	6
cortical plate	6
endothelial cell	5
sural nerve	5
cerebellar cortex	5
primordial germ cell in gonad	4
right uterine tube	4
middle frontal gyrus	3
middle temporal gyrus	3
postcentral gyrus	3
parotid gland	3
stromal cell of endometrium	3
colonic epithelium	3
calcaneal tendon	3
lateral nuclear group of thalamus	3
buccal mucosa cell	3
ganglionic eminence	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PCNA	287	ubiquitous	marker	oocyte, secondary oocyte, ganglionic eminence
SACS	286	ubiquitous	marker	Brodmann (1909) area 23, middle frontal gyrus, frontal pole
SCN8A	194	ubiquitous	marker	Brodmann (1909) area 23, middle temporal gyrus, postcentral gyrus
SEC23B	289	ubiquitous	marker	endothelial cell, islet of Langerhans, parotid gland
SLC6A3	84	tissue_specific	marker	substantia nigra, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad
SPAST	284	ubiquitous	marker	cortical plate, oocyte, secondary oocyte
SPG7	302	ubiquitous	marker	primordial germ cell in gonad, sural nerve, left lobe of thyroid gland
SPTBN2	238	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
SYNGAP1	137	ubiquitous	marker	pituitary gland, right uterine tube, adenohypophysis
NKX2-1	101	broad	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
TRIO	279	ubiquitous	marker	sural nerve, cortical plate, stromal cell of endometrium
USP9X	295	ubiquitous	marker	middle frontal gyrus, endometrium epithelium, secondary oocyte
WASF1	261	ubiquitous	marker	cortical plate, CA1 field of hippocampus, Brodmann (1909) area 23
WFS1	280	ubiquitous	marker	right ovary, left ovary, body of uterus
CACNA1A	237	broad	marker	cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex
ANO3	189	broad	marker	corpus epididymis, lateral globus pallidus, putamen
CIC	274	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
CAMK2B	233	broad	marker	cerebellar cortex, cerebellar hemisphere, right hemisphere of cerebellum
APTX	278	ubiquitous	marker	colonic epithelium, islet of Langerhans, primordial germ cell in gonad
DHX30	245	ubiquitous	marker	left testis, right testis, right hemisphere of cerebellum
LITAF	294	ubiquitous	marker	blood, palpebral conjunctiva, periodontal ligament
MFN2	297	ubiquitous	marker	apex of heart, heart left ventricle, cardiac ventricle
SYNE1	275	ubiquitous	marker	cerebellar hemisphere, right hemisphere of cerebellum, calcaneal tendon
ARID1B	256	ubiquitous	marker	bone marrow cell, colonic epithelium, sural nerve
SETD2	291	ubiquitous	marker	tendon of biceps brachii, endothelial cell, colonic epithelium
DEPDC5	236	ubiquitous	marker	paraflocculus, frontal pole, middle frontal gyrus
CAMTA1	287	ubiquitous	marker	parotid gland, postcentral gyrus, heart right ventricle
TTBK2	275	ubiquitous	marker	lateral nuclear group of thalamus, Brodmann (1909) area 23, pons
CLCN2	181	broad	yes	mucosa of transverse colon, tibial nerve, sural nerve
COL4A2	284	ubiquitous	marker	saphenous vein, decidua, placenta

Protein interactions among cohort

Intra-cohort edges: 24.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALDH18A1	7,351
RANBP2	7,348
PCNA	6,079
POLR3A	4,915
DNM1L	4,801
SETD2	4,668
DHX30	4,364
SPG7	3,970
ATP1A3	3,876
MFN2	3,853

Intra-cohort edges

A	B	Sources
ABCD1	SPAST	string_interaction
ABHD18	MFSD8	string_interaction
ALDH18A1	SPAST	string_interaction
ALG13	ARID1B	biogrid_interaction
ANO3	ATP1A3	string_interaction
ANO3	TOR1A	string_interaction
APTX	NKX2-1	biogrid_interaction
ATP1A3	TOR1A	string_interaction
CAMK2B	SYNGAP1	string_interaction
DNM1L	MFN2	string_interaction
DNM1L	SACS	string_interaction
ITM2B	L1CAM	intact
KCNA1	SCN8A	string_interaction
KCNC3	PRKCG	string_interaction
KCNC3	SPTBN2	string_interaction
KCNC3	TTBK2	string_interaction
KCNJ11	WFS1	string_interaction
KIF1A	WFS1	intact
MT-ATP6	MT-ND6	string_interaction
PKD1	PRKD1	string_interaction
PRKCG	SPTBN2	string_interaction
SPTBN2	TTBK2	string_interaction
SYNE1	TOR1A	string_interaction
SYNGAP1	TRIO	intact

Structural data

PDB: 51 · AlphaFold-only: 14 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PCNA	P12004	102
KIF11	P52732	62
SETD2	Q9BYW2	43
RANBP2	P49792	33
POLR3A	O14802	29
KIF1A	Q12756	21
SLC6A3	Q01959	17
GFPT1	Q06210	16
ABCD1	P33897	14
PKD1	P98161	13
APTX	Q7Z2E3	11
DEPDC5	O75140	11
PNPT1	Q8TCS8	11
DNM1L	O00429	11
HMBS	P08397	11
SLC6A20	Q9NP91	10
MT-ATP6	P00846	10
KCNJ11	Q14654	9
CLCN2	P51788	8
SACS	Q9NZJ4	7
SCN8A	Q9UQD0	7
SPAST	Q9UBP0	7
CIC	Q96RK0	7
TTBK2	Q6IQ55	6
KCND3	Q9UK17	6
WASF1	Q92558	5
KCNQ5	Q9NR82	5
MT-ND6	P03923	5
ATP1A3	P13637	5
TRIO	O75962	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SEC23B	Q15437	92.41
MFSD8	Q8NHS3	83.20
ABHD18	Q0P651	80.82
ZSWIM6	Q9HCJ5	79.99
KCNA1	Q09470	78.74
ANO3	Q9BYT9	76.30
WFS1	O76024	73.85
LITAF	Q99732	70.60
PRKD1	Q15139	68.99
EYA1	Q99502	66.68
KCNC3	Q14003	66.01
SYNGAP1	Q96PV0	60.43
ALG13	Q9NP73	54.42
ASXL3	Q9C0F0	39.70

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 364. Enrichment computed across 67 evidence-associated genes (53 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 53 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Neuronal System	10	8.3×	9e-05	SLC6A3, CACNA1A, CAMK2B, ADCY5, KCNA1, KCNC3, KCND3, KCNJ11 (+2 more)
Voltage gated Potassium channels	4	18.3×	0.008	KCNA1, KCNC3, KCND3, KCNQ5
Potassium Channels	5	12.7×	0.008	KCNA1, KCNC3, KCND3, KCNJ11, KCNQ5
Cardiac conduction	5	10.3×	0.011	SCN8A, CAMK2B, KCND3, KCNJ11, ATP1A3
Transport of small molecules	9	4.3×	0.016	SLC6A3, SPG7, ANO3, CAMK2B, ADCY5, SLC6A20, ABCD1, KCNJ11 (+1 more)
Calmodulin induced events	3	21.6×	0.016	CAMK2B, ADCY5, PRKCG
CaM pathway	3	21.6×	0.016	CAMK2B, ADCY5, PRKCG
Ca-dependent events	3	20.9×	0.016	CAMK2B, ADCY5, PRKCG
Interaction between L1 and Ankyrins	3	20.9×	0.016	SCN8A, SPTBN2, L1CAM
G-protein mediated events	3	18.5×	0.016	CAMK2B, ADCY5, PRKCG
DAG and IP3 signaling	3	18.0×	0.016	CAMK2B, ADCY5, PRKCG
Disorders of transmembrane transporters	4	10.5×	0.016	SLC6A3, SLC6A20, ABCD1, KCNJ11
Muscle contraction	5	7.3×	0.016	SCN8A, CAMK2B, KCND3, KCNJ11, ATP1A3
Transmission across Chemical Synapses	5	7.2×	0.016	SLC6A3, CACNA1A, CAMK2B, ADCY5, PRKCG
Opioid Signalling	3	15.0×	0.023	CAMK2B, ADCY5, PRKCG
PLC beta mediated events	3	15.0×	0.023	CAMK2B, ADCY5, PRKCG
Mitochondrial protein degradation	4	8.6×	0.025	SPG7, MT-ATP6, MT-ND6, ALDH18A1
Regulation of insulin secretion	3	12.4×	0.036	CACNA1A, ADCY5, KCNJ11
Glutamate binding, activation of AMPA receptors and synaptic plasticity	2	28.7×	0.040	CAMK2B, PRKCG
Ion homeostasis	3	11.5×	0.040	CAMK2B, KCNJ11, ATP1A3
Integration of energy metabolism	3	9.9×	0.058	CACNA1A, ADCY5, KCNJ11
Defective HEXA causes GM2G1 (Hyaluronan metabolism)	1	215.5×	0.065	HEXA
Defective GFPT1 causes CMSTA1	1	215.5×	0.065	GFPT1
Defective neurotransmitter clearance by SLC6A3 causes Parkinsonism-dystonia infantile (PKDYS)	1	215.5×	0.065	SLC6A3
Defective transport of neurotransmitters by SLC6A3 causes Parkinsonism-dystonia infantile (PKDYS)	1	215.5×	0.065	SLC6A3
Trafficking of AMPA receptors	2	20.5×	0.065	CAMK2B, PRKCG
ABC transporter disorders	2	16.6×	0.086	ABCD1, KCNJ11
Dopamine clearance from the synaptic cleft	1	107.7×	0.094	SLC6A3
Variant SLC6A20 affecting neurotransmitter transport contributes towards hyperglycinuria (HG) and iminoglycinuria (IG)	1	107.7×	0.094	SLC6A20
Defective ALG14 causes ALG14-CMS	1	107.7×	0.094	ALG13

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 64 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
action potential	5	28.0×	6e-04	SCN8A, KCNA1, KCNC3, KCND3, KCNJ11
mitocytosis	2	87.8×	0.024	DNM1L, PKD1
anterograde axonal transport	3	27.2×	0.024	SPAST, SPG7, KIF1A
rhythmic process	4	15.7×	0.024	NKX2-1, USP9X, DNM1L, PRKCG
potassium ion transmembrane transport	5	10.6×	0.024	KCNA1, KCNC3, KCND3, KCNJ11, KCNQ5
protein homooligomerization	5	9.5×	0.024	SPAST, PNPT1, KCNA1, KCNC3, KCND3
regulation of dendritic spine development	2	52.7×	0.062	CAMK2B, KIF1A
mitochondrion organization	4	9.5×	0.073	WASF1, PNPT1, MFSD8, DNM1L
regulation of resting membrane potential	2	40.5×	0.073	CLCN2, ATP1A3
nervous system process	2	37.6×	0.073	WFS1, KCNJ11
detection of mechanical stimulus	2	37.6×	0.073	ANO3, PKD1
neuromuscular process controlling balance	3	15.5×	0.073	CAMTA1, ADCY5, HEXA
neuron projection maintenance	2	35.1×	0.077	ABCD1, ATP1A3
L-ornithine biosynthetic process	1	263.3×	0.083	ALDH18A1
body morphogenesis	1	263.3×	0.083	GPC3
regulation of aldosterone biosynthetic process	1	263.3×	0.083	CLCN2
RNA import into mitochondrion	1	263.3×	0.083	PNPT1
maintenance of location	1	263.3×	0.083	MFSD8
nuclear polyadenylation-dependent mRNA catabolic process	1	263.3×	0.083	PNPT1
otic vesicle morphogenesis	1	263.3×	0.083	EYA1
metanephric distal tubule morphogenesis	1	263.3×	0.083	PKD1
mitochondrial RNA 5’-end processing	1	131.7×	0.083	PNPT1
glycolipid metabolic process	1	131.7×	0.083	MFSD8
regulation of macrophage cytokine production	1	131.7×	0.083	LITAF
regulation of skeletal muscle contraction by modulation of calcium ion sensitivity of myofibril	1	131.7×	0.083	PRKD1
regulation of skeletal muscle adaptation	1	131.7×	0.083	CAMK2B
amino-acid betaine transport	1	131.7×	0.083	SLC6A20
peroxisomal membrane transport	1	131.7×	0.083	ABCD1
cerebellar Purkinje cell layer morphogenesis	1	131.7×	0.083	SPTBN2
cerebellar granule cell precursor tangential migration	1	131.7×	0.083	TTBK2

Therapeutics

Drug target analysis

Approved (phase 4): 14 · Phase ≥3: 15 · Phased (≥1): 17 · Undrugged: 50

Druggability breadth: 42 of 67 evidence-associated genes (63%) 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
PCNA	LIOTHYRONINE
SCN8A	IMIPRAMINE
SLC6A3	CETIRIZINE
CACNA1A	NIMODIPINE
CAMK2B	FEDRATINIB
AGL	MIGLUSTAT
HEXA	PYRIMETHAMINE
KCNA1	NIFEDIPINE
KCND3	DULOXETINE
KCNJ11	PINACIDIL ANHYDROUS
KCNQ5	EZOGABINE
ATP1A3	OMEPRAZOLE
PRKCG	INGENOL MEBUTATE
PRKD1	INGENOL MEBUTATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC6A3	466	4
PRKD1	26	4
SCN8A	25	4
CAMK2B	25	4
PRKCG	23	4
KCND3	10	4
KCNJ11	7	4
KIF11	6	3
PCNA	5	4
KCNA1	5	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LIOTHYRONINE	4	PCNA
IMIPRAMINE	4	SCN8A, SLC6A3
SERTINDOLE	4	SCN8A, SLC6A3
PIMOZIDE	4	SCN8A, SLC6A3
NIFEDIPINE	4	KCNA1, SCN8A
DILTIAZEM	4	SCN8A
MIBEFRADIL	4	SCN8A, SLC6A3
HALOPERIDOL	4	SCN8A, SLC6A3
MEXILETINE	4	SCN8A
AMITRIPTYLINE	4	SCN8A, SLC6A3
AMIODARONE	4	SCN8A, SLC6A3
CHLORPROMAZINE	4	SCN8A, SLC6A3
TETRACAINE	4	SCN8A, SLC6A3
CETIRIZINE	4	SLC6A3
BEPRIDIL	4	SLC6A3
CANDESARTAN CILEXETIL	4	SLC6A3
BEXAROTENE	4	SLC6A3
CLOTRIMAZOLE	4	SLC6A3
AMINOCAPROIC ACID	4	SLC6A3
SIMVASTATIN	4	SLC6A3
NABUMETONE	4	SLC6A3
PROPIVERINE	4	SLC6A3
ACETOPHENAZINE	4	SLC6A3
MESORIDAZINE	4	SLC6A3
VALPROIC ACID	4	SLC6A3
NIRAPARIB	4	SLC6A3
INDACATEROL	4	SLC6A3
HALOFANTRINE	4	SLC6A3
RIMONABANT	4	SLC6A3
ARIPIPRAZOLE	4	SLC6A3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 18.

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

Symbol	Assays	Type breakdown
SLC6A3	1,043	Binding:993, Functional:24, ADMET:24, Toxicity:2
PRKD1	660	Binding:650, Functional:10
PRKCG	627	Binding:611, Functional:15, ADMET:1
CAMK2B	314	Binding:313, Functional:1
KIF11	193	Binding:185, Functional:8
SCN8A	173	Binding:148, Functional:16, ADMET:7, Toxicity:2
KCND3	118	Binding:55, Functional:44, ADMET:12, Toxicity:7
KCNJ11	102	Functional:59, Binding:43
SETD2	64	Binding:64
KCNA1	59	Binding:52, Functional:6, Toxicity:1
HEXA	58	Binding:58
TTBK2	56	Binding:56
ATP1A3	45	Binding:45
ADCY5	43	Binding:33, Functional:9, ADMET:1
USP9X	41	Binding:41
KCNQ5	40	Binding:35, Functional:2, ADMET:2, Toxicity:1
PKD1	27	Binding:27
PCNA	21	Binding:21
KCNC3	21	Binding:20, Toxicity:1
CACNA1A	19	Binding:18, Functional:1
GFPT1	8	Binding:8
GPC3	5	Binding:5
DNM1L	4	Binding:4
AGL	4	Binding:4
MT-ND6	4	Binding:4
MFN2	3	Binding:3
HMBS	3	Binding:3
ALDH18A1	3	Binding:3
TRIO	2	Binding:2
L1CAM	2	Binding:2
KIF1A	2	Binding:2
SEC23B	1	Binding:1
SPAST	1	Binding:1
WFS1	1	Binding:1
APTX	1	Binding:1
DHX30	1	Binding:1
LITAF	1	Binding:1
CLCN2	1	Binding:1
MT-ATP6	1	Binding:1
RANBP2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SPAST	5.6.1.1	microtubule-severing ATPase
SPG7	3.4.24.B18
CAMK2B	2.7.11.17	Ca2+/calmodulin-dependent protein kinase
APTX	3.1.11.7, 3.6.1.70, 3.6.1.71, 3.6.1.72	adenosine-5’-diphospho-5’-[DNA] diphosphatase, guanosine-5’-diphospho-5’-[DNA] diphosphatase, adenosine-5’-diphospho-5’-[DNA] diphosphatase, DNA-3’-diphospho-5’-guanosine diphosphatase
SETD2	2.1.1.359	[histone H3]-lysine36 N-trimethyltransferase
TTBK2	2.7.11.26	tau-protein kinase
PNPT1	2.7.7.8	polyribonucleotide nucleotidyltransferase
ADCY5	4.6.1.1	adenylate cyclase
DNM1L	3.6.5.5	dynamin GTPase
AGL	3.2.1.33	amylo-alpha-1,6-glucosidase
GFPT1	2.6.1.16	glutamine-fructose-6-phosphate transaminase (isomerizing)
HEXA	3.2.1.169	protein O-GlcNAcase
HMBS	2.5.1.61	hydroxymethylbilane synthase
ABCD1	7.6.2.4	ABC-type fatty-acyl-CoA transporter
KIF11	5.6.1.3	plus-end-directed kinesin ATPase
KIF1A	5.6.1.3	plus-end-directed kinesin ATPase
PRKCG	2.7.11.13	protein kinase C
PRKD1	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
SLC6A3	1,043
CAMK2B	314
KCND3	118
KCNJ11	102
KIF11	193
PRKCG	627
PRKD1	660

Pharmacogenomics

Cohort genes with a PharmGKB record: 65; 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)
LIOTHYRONINE	4	PCNA
IMIPRAMINE	4	SCN8A, SLC6A3
SERTINDOLE	4	SCN8A, SLC6A3
PIMOZIDE	4	SCN8A, SLC6A3
NIFEDIPINE	4	KCNA1, SCN8A
DILTIAZEM	4	SCN8A
MIBEFRADIL	4	SCN8A, SLC6A3
HALOPERIDOL	4	SCN8A, SLC6A3
MEXILETINE	4	SCN8A
AMITRIPTYLINE	4	SCN8A, SLC6A3
AMIODARONE	4	SCN8A, SLC6A3
CHLORPROMAZINE	4	SCN8A, SLC6A3
TETRACAINE	4	SCN8A, SLC6A3
CETIRIZINE	4	SLC6A3
BEPRIDIL	4	SLC6A3
CANDESARTAN CILEXETIL	4	SLC6A3
BEXAROTENE	4	SLC6A3
CLOTRIMAZOLE	4	SLC6A3
AMINOCAPROIC ACID	4	SLC6A3
SIMVASTATIN	4	SLC6A3
NABUMETONE	4	SLC6A3
PROPIVERINE	4	SLC6A3
ACETOPHENAZINE	4	SLC6A3
MESORIDAZINE	4	SLC6A3
VALPROIC ACID	4	SLC6A3
NIRAPARIB	4	SLC6A3
INDACATEROL	4	SLC6A3
HALOFANTRINE	4	SLC6A3
RIMONABANT	4	SLC6A3
ARIPIPRAZOLE	4	SLC6A3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	14	PCNA, SCN8A, SLC6A3, CACNA1A, CAMK2B, AGL, HEXA, KCNA1, KCND3, KCNJ11 (+4 more)
B	Phased (≥1) drug, not yet approved	3	USP9X, SETD2, KIF11
C	Druggable family + PDB, no drug	13	SPAST, SPG7, TRIO, CAMTA1, TTBK2, ADCY5, DNM1L, GFPT1, HMBS, ABCD1 (+3 more)
D	Druggable family + AlphaFold only, no drug	2	MFSD8, KCNC3
E	Difficult family or no structure, no drug	35	SACS, SEC23B, SPTBN2, SYNGAP1, NKX2-1, WASF1, WFS1, ANO3, CIC, APTX (+25 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PKD1	27	PRKD1
SACS	0	—
SEC23B	1	—
SPAST	1	—
SPG7	0	—
SPTBN2	0	—
SYNGAP1	0	—
NKX2-1	0	—
TRIO	2	—
WASF1	0	—
WFS1	1	—
ANO3	0	—
CIC	0	—
APTX	1	—
DHX30	1	—
LITAF	1	—
MFN2	3	—
SYNE1	0	—
ARID1B	0	—
DEPDC5	0	—
CAMTA1	0	—
TTBK2	56	—
CLCN2	1	—
COL4A2	0	—
PNPT1	0	—
ADCY5	43	—
ABHD18	0	—
LINC00964	0	—
MFSD8	0	—
ZSWIM6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 12.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	10
PHASE2	1
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00202397	PHASE2	COMPLETED	Effect of Riluzole as a Symptomatic Approach in Patients With Chronic Cerebellar Ataxia
NCT01360164	PHASE1/PHASE2	UNKNOWN	Safety and Efficacy of Umbilical Cord Mesenchymal Stem Cell Therapy for Patients With Hereditary Ataxia
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT06034886	Not specified	AVAILABLE	Expanded Access Protocol of Troriluzole in Patients With Spinocerebellar Ataxia (SCA)
NCT06267222	Not specified	ENROLLING_BY_INVITATION	Trans-spinal Electrical Stimulation in Individuals With Spinocerebellar Ataxia
NCT07092358	Not specified	RECRUITING	Hereditary Ataxia Research on Multi-Omics and Neuroclinical Insights in the Yangtze Delta
NCT07200505	Not specified	NOT_YET_RECRUITING	Telerehabilitation for Core Stability and Strength in Hereditary Ataxia
NCT00004306	Not specified	COMPLETED	Clinical and Molecular Correlations in Spinocerebellar Ataxia Type 10 (SCA10)
NCT04750850	Not specified	COMPLETED	Core Stability Exercises and Hereditary Ataxia
NCT05160870	Not specified	UNKNOWN	Genotype-phenotype Correlation and Pathogenic Mechanism in Hereditary Ataxia
NCT05160883	Not specified	UNKNOWN	Neuroimaging Changes in Hereditary Ataxia
NCT06152133	Not specified	COMPLETED	Telerehabilitation, Core Stability Exercises and Hereditary Ataxia (TRCore-ataxia)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
RILUZOLE	4	1
TRORILUZOLE	3	1