Epilepsy

Summary

Epilepsy (MONDO:0005027) is a disease (an umbrella term covering 13 Mondo subtypes) caused by variants in GABRG2, BSN, and KCNA1, with 75 cohort genes (92 GWAS associations across 70 studies) and 1,421 clinical trials. The dominant Reactome pathway is Neuronal System (19 cohort genes). Top therapeutic interventions include lacosamide, eslicarbazepine acetate, and levetiracetam.

At a glance

• Causal genes: GABRG2 (GenCC Definitive), BSN (GenCC Strong), KCNA1 (GenCC Strong)
• Umbrella term: 13 Mondo subtypes
• Cohort genes: 75
• GWAS associations: 92
• ClinVar variants: 853
• Clinical trials: 1,421

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	epilepsy
Mondo ID	MONDO:0005027
EFO	EFO:0000474
MeSH	D004827
DOID	DOID:1826
ICD-10-CM	G40
NCIT	C3020
SNOMED CT	84757009
UMLS	C0014544
MedGen	4506
Is cancer (heuristic)	no

Also known as: epilepsy · seizure disorder

Data availability: 853 ClinVar variants · 92 GWAS associations (70 studies) · 32 GenCC gene-disease records · 1,073 cell lines.

Disease family

An umbrella term covering 13 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › epilepsy

Related subtypes (70): leukoencephalopathy, megalencephalic, encephalopathy, acute, infection-induced, diabetic encephalopathy, complex cortical dysplasia with other brain malformations, hydrocephalus, brain compression, cerebral sarcoidosis, hepatic encephalopathy, visual pathway disorder, central nervous system origin vertigo, cerebellar disorder, cerebritis, olfactory nerve disorder, thalamic disorder, pituitary gland disorder, disorder of optic chiasm, basal ganglia disorder, mental disorder, central nervous system cyst, migraine disorder, multiple sclerosis, prion disease, carbon monoxide-induced delayed encephalopathy, cerebral malaria, akinetic mutism, bulbar polio, Reye syndrome, brain edema, encephalomalacia, intracranial hypertension, intracranial hypotension, Wernicke encephalopathy, encephalopathy, recurrent, of childhood, XK aprosencephaly, progressive bulbar palsy, cerebrovascular disorder, glycine encephalopathy, autosomal recessive frontotemporal pachygyria, occipital pachygyria and polymicrogyria, insomnia, narcolepsy-cataplexy syndrome, megalencephaly, meningoencephalocele, cerebral cortical dysplasia, encephaloclastic disorder, bilirubin encephalopathy, autoimmune encephalopathy with parasomnia and obstructive sleep apnea, narcolepsy without cataplexy, hypothalamic hamartomas with gelastic seizures, encephalitis, cerebral lipidosis with dementia, brain neoplasm, colpocephaly, corpus callosum agenesis of blepharophimosis robin type, corpus callosum dysgenesis X-linked recessive, corpus callosum dysgenesis cleft spasm, corpus callosum dysgenesis hypopituitarism, cerebral degeneration, acute bilirubin encephalopathy, chronic bilirubin encephalopathy, atelencephaly, aprosencephaly, brain injury, traumatic encephalopathy, cluster headache syndrome, cerebral cortex disorder, midbrain disorder, encephalopathy due to mitochondrial and peroxisomal fission defect, brain malformations with or without urinary tract defects, encephalopathy, acute transient

Subtypes (13): extratemporal epilepsy, focal epilepsy, epilepsy syndrome, monogenic epilepsy, reflex epilepsy, post-traumatic epilepsy, immune epilepsy, metabolic epilepsy, structural epilepsy, infantile-onset epilepsy, generalized epilepsy, epilepsy, unknown whether focal or generalized, developmental and epileptic encephalopathy

Genetics & variants

GWAS landscape

92 GWAS associations across 70 studies. Top hits map to 23 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs13032423	9e-17	ACTG1P22	G	0.85
rs6432877	2e-13	SCN1A, SCN1A-AS1	G	7.37
rs11890028	8e-13	SCN1A-AS1, SCN1A	T	1.08
rs3740422	2e-12	OGA	G	1.15
rs59237858	6e-12	SCN1A-AS1, SCN1A	T
rs186028145	1e-11	AUTS2	G	3.19
rs73151649	2e-11	ZNF217 - RNU7-14P	G	4.4
rs9596863	8e-11	LINC00558	G	15.2
rs74308953	2e-10	TPT1P9 - LINC02578	A	4.6
rs79007183	3e-10	CRAMP1	A	14
rs60055328	3e-10	SCN1A, SCN1A-AS1	C	1.07
rs6732655	9e-10	SCN1A, SCN1A-AS1	T	1.12
rs149212747	9e-10	LINC02356	?	1.38
rs7495694	1e-09	ADPGK-AS1 - NPM1P42	G	7.6
rs74912790	1e-09	IFNA6 - MIR31HG	A	10.7
rs13026414	2e-09	EIF2S2P7 - ACTG1P22	C	1.23
rs71568191	3e-09	NPM1P10 - HACE1	A	8.9
rs66614071	3e-09	CUX2	?	0.69
rs79105258	3e-09	CUX2	?	0.75
rs9596837	4e-09	ZNF646P1 - LINC00558	?	10.1
rs28498976	5e-09	PCDH7 - LINC02497	A	1.11
rs11066001	5e-09	BRAP	?	0.69
rs4646776	5e-09	ALDH2	?	0.69
rs7328626	8e-09	ZNF646P1 - LINC00558	?	9.7
rs55949311	8e-09	ZNF646P1 - LINC00558	?	9.7
rs4671319	8e-09	EIF2S2P7 - ACTG1P22	G	5.77
rs1960242	8e-09	SCN1A, SCN1A-AS1	T
rs72823592	9e-09	NFE2L1-DT	G	1.3
rs10496964	9e-09	LINC01412	C	1.47
rs11978015	9e-09	SOCS5P1 - GRM3	G	1.06

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90271608	International League Against Epilepsy Consortium on Complex Epilepsies	2023	27,559	42,436	GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture.
GCST90271611	International League Against Epilepsy Consortium on Complex Epilepsies	2023	27,559	42,436	GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture.
GCST90027898	Song M	2021	19,122	168,998	Genome-Wide Meta-Analysis Identifies Two Novel Risk Loci for Epilepsy.
GCST007343	International League Against Epilepsy Consortium on Complex Epilepsies	2018	14,534	24,218	Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies.
GCST90281291	International League Against Epilepsy Consortium on Complex Epilepsies	2023	13,889	19,676	GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture.
GCST90473322	UK Biobank Whole-Genome Sequencing Consortium	2025	8,269	450,171	Whole-genome sequencing of 490,640 UK Biobank participants.
GCST90281287	International League Against Epilepsy Consortium on Complex Epilepsies	2023	6,952	42,434	GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture.
GCST90476931	Verma A	2024	6,205	309,463	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90477550	Verma A	2024	6,189	112,569	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90435926	Zhou W	2018	5,087	395,209	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	2
Tier 4: intronic/intergenic	48

MAF distribution

Bucket	Variants
common (>=0.05)	32
low_freq (0.01-0.05)	13
rare (<0.01)	3
unknown	2

Functional consequences

Consequence	Count
intron_variant	34
intergenic_variant	12
non_coding_transcript_exon_variant	2
regulatory_region_variant	2

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs13032423	2	57764977	G>A	0.05	non_coding_transcript_exon_variant	ACTG1P22	9e-17	Tier 4: intronic/intergenic
rs6432877	2	166142257	C>A,G,T	0.26	intron_variant	SCN1A, SCN1A-AS1	2e-13	Tier 4: intronic/intergenic
rs11890028	2	166086767	T>A,G	0.05	intron_variant	SCN1A-AS1, SCN1A	8e-13	Tier 4: intronic/intergenic
rs3740422	10	101806203	G>C	0.05	intron_variant	OGA	2e-12	Tier 4: intronic/intergenic
rs59237858	2	166084257	C>A,T	0.05	intron_variant	SCN1A-AS1, SCN1A	6e-12	Tier 4: intronic/intergenic
rs186028145	7	70748549	G>A,T	0	intron_variant	AUTS2	1e-11	Tier 4: intronic/intergenic
rs73151649	20	53655186	G>A	0	intron_variant	ZNF217 - RNU7-14P	2e-11	Tier 4: intronic/intergenic
rs9596863	13	53860512	T>A,G	0.01	intron_variant	LINC00558	8e-11	Tier 4: intronic/intergenic
rs74308953	9	118668911	G>A,C	0.12	intergenic_variant	TPT1P9 - LINC02578	2e-10	Tier 4: intronic/intergenic
rs79007183	16	1655793	G>A,T	0.01	intron_variant	CRAMP1	3e-10	Tier 4: intronic/intergenic
rs60055328	2	166084289	T>C	0.05	intron_variant	SCN1A, SCN1A-AS1	3e-10	Tier 4: intronic/intergenic
rs6732655	2	166038556	A>T	0.22	intron_variant	SCN1A, SCN1A-AS1	9e-10	Tier 4: intronic/intergenic
rs149212747	12	111398968	AC>A,ACC,ACCC	0.05	intron_variant	LINC02356	9e-10	Tier 4: intronic/intergenic
rs7495694	15	72833651	A>G,T	0.02	intergenic_variant	ADPGK-AS1 - NPM1P42	1e-09	Tier 4: intronic/intergenic
rs74912790	9	21354067	G>A	0.01	intergenic_variant	IFNA6 - MIR31HG	1e-09	Tier 4: intronic/intergenic
rs13026414	2	57706920	C>T	0.424	intron_variant	EIF2S2P7 - ACTG1P22	2e-09	Tier 4: intronic/intergenic
rs71568191	6	104230957	G>A	0.01	intergenic_variant	NPM1P10 - HACE1	3e-09	Tier 4: intronic/intergenic
rs66614071	12	111170442	GAAA>G,GA,GAA,GAAAA,GAAAAA,GAAAAAA,GAAAAAAA,GAAAAAAAA	0.05	intron_variant	CUX2	3e-09	Tier 4: intronic/intergenic
rs79105258	12	111280427	C>A,T	0.05	intron_variant	CUX2	3e-09	Tier 4: intronic/intergenic
rs9596837	13	53683928	T>C	0.01	intron_variant	ZNF646P1 - LINC00558	4e-09	Tier 4: intronic/intergenic
rs28498976	4	31149735	G>A	0.46	intergenic_variant	PCDH7 - LINC02497	5e-09	Tier 4: intronic/intergenic
rs11066001	12	111681367	T>C	0.05	intron_variant	BRAP	5e-09	Tier 4: intronic/intergenic
rs4646776	12	111792215	G>A,C	0.05	intron_variant	ALDH2	5e-09	Tier 4: intronic/intergenic
rs7328626	13	53576772	G>A,T	0.01	intron_variant	ZNF646P1 - LINC00558	8e-09	Tier 4: intronic/intergenic
rs55949311	13	53557781	G>A,C,T	0.01	intron_variant	ZNF646P1 - LINC00558	8e-09	Tier 4: intronic/intergenic
rs4671319	2	57723211	G>A,T	0.44	intron_variant	EIF2S2P7 - ACTG1P22	8e-09	Tier 4: intronic/intergenic
rs1960242	2	166133537	G>C,T	0.05	intron_variant	SCN1A, SCN1A-AS1	8e-09	Tier 4: intronic/intergenic
rs72823592	17	48045642	G>A,C	0.247	regulatory_region_variant	NFE2L1-DT	9e-09	Tier 3: regulatory
rs10496964	2	144602342	C>A,T	0.156	intron_variant	LINC01412	9e-09	Tier 4: intronic/intergenic
rs11978015	7	86348656	G>A,T	0.05	intergenic_variant	SOCS5P1 - GRM3	9e-09	Tier 4: intronic/intergenic

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

240 likely benign, 239 uncertain significance, 51 pathogenic, 29 conflicting classifications of pathogenicity, 14 pathogenic/likely pathogenic, 11 benign, 11 likely pathogenic, 5 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
223117	Single allele	ACR	Pathogenic	no assertion criteria provided
280045	NM_001182.5(ALDH7A1):c.1489+5G>A	ALDH7A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2571331	NM_001195248.2(APTX):c.739C>T (p.Arg247Ter)	APTX	Pathogenic	criteria provided, multiple submitters, no conflicts
2425036	NC_000016.9:g.(?256302)(633035_?)del	ARHGDIG	Pathogenic	criteria provided, single submitter
37110	NM_152296.5(ATP1A3):c.2839G>A (p.Gly947Arg)	ATP1A3	Pathogenic	criteria provided, multiple submitters, no conflicts
3076079	NM_001271.4(CHD2):c.1719+1G>A	CHD2	Pathogenic	criteria provided, single submitter
1810256	NM_001242896.3(DEPDC5):c.1093_1103del (p.Asp365fs)	DEPDC5	Pathogenic	criteria provided, single submitter
3235899	NM_001242896.3(DEPDC5):c.687del (p.Lys229fs)	DEPDC5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3384069	NM_001242896.3(DEPDC5):c.1237C>T (p.Gln413Ter)	DEPDC5	Pathogenic	criteria provided, single submitter
183344	NM_005219.5(DIAPH1):c.2332C>T (p.Gln778Ter)	DIAPH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
254261	NM_000814.6(GABRB3):c.358G>A (p.Asp120Asn)	GABRB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16208	NM_198904.4(GABRG2):c.245G>A (p.Arg82Gln)	GABRG2	Pathogenic	criteria provided, multiple submitters, no conflicts
1489402	NM_001134407.3(GRIN2A):c.2168+1G>C	GRIN2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
374226	NM_000834.5(GRIN2B):c.2116A>G (p.Met706Val)	GRIN2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
223119	Single allele	HDAC10	Pathogenic	no assertion criteria provided
449693	NM_004975.4(KCNB1):c.916C>T (p.Arg306Cys)	KCNB1	Pathogenic	criteria provided, multiple submitters, no conflicts
3600985	NM_001378969.1(KCND3):c.1201G>C (p.Val401Leu)	KCND3	Pathogenic	criteria provided, single submitter
372677	NM_172107.4(KCNQ2):c.1679G>A (p.Arg560Gln)	KCNQ2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
126421	NM_020822.3(KCNT1):c.862G>A (p.Gly288Ser)	KCNT1	Pathogenic	criteria provided, multiple submitters, no conflicts
3336823	NM_001165963.4(SCN1A):c.5547_5548insGC (p.Ile1850fs)	LOC102724058	Pathogenic	criteria provided, single submitter
14278	NM_000254.3(MTR):c.3518C>T (p.Pro1173Leu)	MTR	Pathogenic	criteria provided, multiple submitters, no conflicts
375701	NM_016023.5(OTUD6B):c.343C>T (p.Arg115Ter)	OTUD6B	Pathogenic	criteria provided, multiple submitters, no conflicts
375702	NM_016023.5(OTUD6B):c.379_383del (p.Leu127fs)	OTUD6B	Pathogenic	criteria provided, single submitter
375703	NM_016023.5(OTUD6B):c.83-2A>G	OTUD6B	Pathogenic	criteria provided, single submitter
206364	NM_001184880.2(PCDH19):c.1019A>G (p.Asn340Ser)	PCDH19	Pathogenic	criteria provided, multiple submitters, no conflicts
1070292	NM_004204.5(PIGQ):c.211C>T (p.Gln71Ter)	PIGQ	Pathogenic	criteria provided, single submitter
1324910	NM_004204.5(PIGQ):c.241del (p.Leu81fs)	PIGQ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1365801	NM_004204.5(PIGQ):c.1024C>T (p.Gln342Ter)	PIGQ	Pathogenic	criteria provided, single submitter
1369604	NM_004204.5(PIGQ):c.91_106del (p.Val31fs)	PIGQ	Pathogenic	criteria provided, single submitter
1387773	NM_004204.5(PIGQ):c.551del (p.Gly184fs)	PIGQ	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 114 · Orphanet: 130 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 4

Dual-evidence genes (GWAS + Mendelian — highest-confidence targets)

Gene	HGNC	Evidence routes
SCN1A	SCN1A	GWAS, Orphanet
SCN2A	SCN2A	GWAS, Orphanet
SCN3A	SCN3A	GWAS, Orphanet
TTC21B	TTC21B	GWAS, Orphanet

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
GABRG2	Definitive	Autosomal dominant	epilepsy	11
BSN	Strong	Autosomal dominant	epilepsy	4
KCNA1	Strong	Autosomal dominant	epilepsy	10
PRICKLE1	Strong	Autosomal recessive	epilepsy, progressive myoclonic, 1B	4
SCN9A	Strong	Autosomal dominant	generalized epilepsy with febrile seizures plus, type 7	16
KCNJ3	Moderate	Autosomal dominant	epilepsy
MICAL1	Moderate	Autosomal dominant	autosomal dominant epilepsy with auditory features	2
ADRA2B	Supportive	Autosomal dominant	benign adult familial myoclonic epilepsy	4
CRH	Supportive	Autosomal dominant	autosomal dominant nocturnal frontal lobe epilepsy	3
ACMSD	Limited	Autosomal dominant	epilepsy
AGBL2	Limited	Autosomal recessive	epilepsy
APBA2	Limited	Autosomal dominant	epilepsy
CCDC22	Limited	X-linked	epilepsy	6
CELSR1	Limited	Autosomal dominant	epilepsy	6
EFHC1	Limited	Autosomal dominant	juvenile myoclonic epilepsy	2
GABRA6	Limited	Autosomal dominant	epilepsy
KCNH7	Limited	Autosomal dominant	epilepsy
PLEKHG2	Limited	Autosomal dominant	epilepsy	5
RBFOX1	Limited	Autosomal dominant	epilepsy	4
RBFOX3	Limited	Autosomal dominant	epilepsy	2
SCAMP5	Limited	Autosomal recessive	epilepsy	4
SEC24D	Limited	Autosomal recessive	epilepsy	8
SLC7A6OS	Limited	Autosomal recessive	epilepsy	3
SLITRK3	Limited	Autosomal dominant	epilepsy	2
SV2A	Limited	Autosomal dominant	epilepsy	3
UNC13B	Limited	Autosomal dominant	epilepsy	2
ZFHX3	Limited	Autosomal recessive	epilepsy	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SCN1A	Orphanet:1942	Epilepsy with myoclonic-atonic seizures
SCN1A	Orphanet:2382	Lennox-Gastaut syndrome
SCN1A	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
SCN1A	Orphanet:33069	Dravet syndrome
SCN1A	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN1A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
SCN1A	Orphanet:569	Familial or sporadic hemiplegic migraine
SCN2A	Orphanet:140927	Self-limited neonatal-infantile epilepsy
SCN2A	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
SCN2A	Orphanet:2131	Alternating hemiplegia of childhood
SCN2A	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
SCN2A	Orphanet:306	Self-limited infantile epilepsy
SCN2A	Orphanet:33069	Dravet syndrome
SCN2A	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN2A	Orphanet:697160	Infantile epileptic spasms syndrome
SCN3A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
SCN3A	Orphanet:98820	Familial focal epilepsy with variable foci
SCN9A	Orphanet:306577	Hereditary sodium channelopathy-related small fibers neuropathy
SCN9A	Orphanet:33069	Dravet syndrome
SCN9A	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN9A	Orphanet:46348	Paroxysmal extreme pain disorder
SCN9A	Orphanet:88642	Congenital insensitivity to pain-anosmia-neuropathic arthropathy
SCN9A	Orphanet:90026	Primary erythromelalgia
SCN9A	Orphanet:970	Hereditary sensory and autonomic neuropathy type 2
TTC21B	Orphanet:474	Jeune syndrome
TTC21B	Orphanet:93591	Infantile nephronophthisis
GABRG2	Orphanet:1945	Self-limited epilepsy with centrotemporal spikes
GABRG2	Orphanet:33069	Dravet syndrome
GABRG2	Orphanet:36387	Genetic epilepsy with febrile seizure plus
GABRG2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
GABRG2	Orphanet:64280	Childhood absence epilepsy
SEC24D	Orphanet:2050	Cole-Carpenter syndrome
SEC24D	Orphanet:216796	Osteogenesis imperfecta type 1
EFHC1	Orphanet:1941	Juvenile absence epilepsy
EFHC1	Orphanet:307	Juvenile myoclonic epilepsy
PRICKLE1	Orphanet:308	Progressive myoclonic epilepsy type 1
CELSR1	Orphanet:569816	CELSR1-related late-onset primary lymphedema
MICAL1	Orphanet:101046	Epilepsy with auditory features
CRH	Orphanet:98784	Sleep-related hypermotor epilepsy
ADRA2B	Orphanet:86814	Familial adult myoclonic epilepsy
CCDC22	Orphanet:7	3C syndrome
KCNA1	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
KCNA1	Orphanet:199326	Isolated autosomal dominant hypomagnesemia, Glaudemans type
KCNA1	Orphanet:37612	Episodic ataxia type 1
KCNA1	Orphanet:972	Hereditary continuous muscle fiber activity
KCNA1	Orphanet:98809	Paroxysmal kinesigenic dyskinesia
KCNJ3	Orphanet:334	Hereditary atrial fibrillation
RYR1	Orphanet:169186	Autosomal recessive centronuclear myopathy
RYR1	Orphanet:169189	Autosomal dominant centronuclear myopathy
RYR1	Orphanet:178145	Moderate multiminicore disease with hand involvement

Cohort genes → proteins

75 cohort genes, 75 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	15
gwas_and_clinvar	4
multi_evidence	56

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCN1A	HGNC:10585	ENSG00000144285	P35498	Sodium channel protein type 1 subunit alpha	gwas,clinvar
SCN2A	HGNC:10588	ENSG00000136531	Q99250	Sodium channel protein type 2 subunit alpha	gwas,clinvar
SCN3A	HGNC:10590	ENSG00000153253	Q9NY46	Sodium channel protein type 3 subunit alpha	gwas,clinvar
SCN9A	HGNC:10597	ENSG00000169432	Q15858	Sodium channel protein type 9 subunit alpha	gencc,clinvar
BSN	HGNC:1117	ENSG00000164061	Q9UPA5	Protein bassoon	gencc,clinvar
TTC21B	HGNC:25660	ENSG00000123607	Q7Z4L5	Tetratricopeptide repeat protein 21B	gwas,clinvar
AGBL2	HGNC:26296	ENSG00000165923	Q5U5Z8	Cytosolic carboxypeptidase 2	gencc,clinvar
GABRG2	HGNC:4087	ENSG00000113327	P18507	Gamma-aminobutyric acid receptor subunit gamma-2	gencc,clinvar
SEC24D	HGNC:10706	ENSG00000150961	O94855	Protein transport protein Sec24D	gencc
UNC13B	HGNC:12566	ENSG00000198722	O14795	Protein unc-13 homolog B	gencc
EFHC1	HGNC:16406	ENSG00000096093	Q5JVL4	EF-hand domain-containing protein 1	gencc
PRICKLE1	HGNC:17019	ENSG00000139174	Q96MT3	Prickle-like protein 1	gencc
RBFOX1	HGNC:18222	ENSG00000078328	Q9NWB1	RNA binding protein fox-1 homolog 1	gencc
CELSR1	HGNC:1850	ENSG00000075275	Q9NYQ6	Cadherin EGF LAG seven-pass G-type receptor 1	gencc
KCNH7	HGNC:18863	ENSG00000184611	Q9NS40	Voltage-gated inwardly rectifying potassium channel KCNH7	gencc
ACMSD	HGNC:19288	ENSG00000153086	Q8TDX5	2-amino-3-carboxymuconate-6-semialdehyde decarboxylase	gencc
SV2A	HGNC:20566	ENSG00000159164	Q7L0J3	Synaptic vesicle glycoprotein 2A	gencc
MICAL1	HGNC:20619	ENSG00000135596	Q8TDZ2	[F-actin]-monooxygenase MICAL1	gencc
SLITRK3	HGNC:23501	ENSG00000121871	O94933	SLIT and NTRK-like protein 3	gencc
CRH	HGNC:2355	ENSG00000147571	P06850	Corticoliberin	gencc
SLC7A6OS	HGNC:25807	ENSG00000103061	Q96CW6	Probable RNA polymerase II nuclear localization protein SLC7A6OS	gencc
RBFOX3	HGNC:27097	ENSG00000167281	A6NFN3	RNA binding protein fox-1 homolog 3	gencc
ADRA2B	HGNC:282	ENSG00000274286	P18089	Alpha-2B adrenergic receptor	gencc
CCDC22	HGNC:28909	ENSG00000101997	O60826	Coiled-coil domain-containing protein 22	gencc
PLEKHG2	HGNC:29515	ENSG00000090924	Q9H7P9	Pleckstrin homology domain-containing family G member 2	gencc
SCAMP5	HGNC:30386	ENSG00000198794	Q8TAC9	Secretory carrier-associated membrane protein 5	gencc
GABRA6	HGNC:4080	ENSG00000145863	Q16445	Gamma-aminobutyric acid receptor subunit alpha-6	gencc
APBA2	HGNC:579	ENSG00000034053	Q99767	Amyloid-beta A4 precursor protein-binding family A member 2	gencc
KCNA1	HGNC:6218	ENSG00000111262	Q09470	Potassium voltage-gated channel subfamily A member 1	gencc
KCNJ3	HGNC:6264	ENSG00000162989	P48549	G protein-activated inward rectifier potassium channel 1	gencc
ZFHX3	HGNC:777	ENSG00000140836	Q15911	Zinc finger homeobox protein 3	gencc
RORB	HGNC:10259	ENSG00000198963	Q92753	Nuclear receptor ROR-beta	clinvar
RYR1	HGNC:10483	ENSG00000196218	P21817	Ryanodine receptor 1	clinvar
SCN8A	HGNC:10596	ENSG00000196876	Q9UQD0	Sodium channel protein type 8 subunit alpha	clinvar
BRAP	HGNC:1099	ENSG00000089234	Q7Z569	BRCA1-associated protein	gwas
SLC2A1	HGNC:11005	ENSG00000117394	P11166	Solute carrier family 2, facilitated glucose transporter member 1	clinvar
SOX1	HGNC:11189	ENSG00000182968	O00570	Transcription factor SOX-1	clinvar
BTD	HGNC:1122	ENSG00000169814	P43251	Biotinidase	clinvar
SYN1	HGNC:11494	ENSG00000008056	P17600	Synapsin-1	clinvar
SYT2	HGNC:11510	ENSG00000143858	Q8N9I0	Synaptotagmin-2	gwas
TSC1	HGNC:12362	ENSG00000165699	Q92574	Hamartin	clinvar
TSC2	HGNC:12363	ENSG00000103197	P49815	Tuberin	clinvar
TSHR	HGNC:12373	ENSG00000165409	P16473	Thyrotropin receptor	clinvar
DNAJC7	HGNC:12392	ENSG00000168259	Q99615	DnaJ homolog subfamily C member 7	clinvar
ACR	HGNC:126	ENSG00000100312	P10323	Acrosin	clinvar
WWOX	HGNC:12799	ENSG00000186153	Q9NZC7	WW domain-containing oxidoreductase	clinvar
BCL11A	HGNC:13221	ENSG00000119866	Q9H165	BCL11 transcription factor A	gwas
ATP8A2	HGNC:13533	ENSG00000132932	Q9NTI2	Phospholipid-transporting ATPase IB	clinvar
FRRS1L	HGNC:1362	ENSG00000260230	Q9P0K9	DOMON domain-containing protein FRRS1L	clinvar
MACF1	HGNC:13664	ENSG00000127603	O94854	Microtubule-actin cross-linking factor 1, isoforms 6/7	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCN1A	Sodium channel protein type 1 subunit alpha	Pore-forming subunit of Nav1.1, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
SCN2A	Sodium channel protein type 2 subunit alpha	Mediates the voltage-dependent sodium ion permeability of excitable membranes.
SCN3A	Sodium channel protein type 3 subunit alpha	Pore-forming subunit of Nav1.3, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
SCN9A	Sodium channel protein type 9 subunit alpha	Pore-forming subunit of Nav1.7, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
BSN	Protein bassoon	Scaffold protein of the presynaptic cytomatrix at the active zone (CAZ) which is the place in the synapse where neurotransmitter is released.
TTC21B	Tetratricopeptide repeat protein 21B	Component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport and entry into cilia of G protein-coupled receptors (GPCRs).
AGBL2	Cytosolic carboxypeptidase 2	Metallocarboxypeptidase that mediates deglutamylation of tubulin and non-tubulin target proteins.
GABRG2	Gamma-aminobutyric acid receptor subunit gamma-2	Gamma subunit of the heteropentameric ligand-gated chloride channel gated by gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain.
SEC24D	Protein transport protein Sec24D	Component of the coat protein complex II (COPII) which promotes the formation of transport vesicles from the endoplasmic reticulum (ER).
UNC13B	Protein unc-13 homolog B	Plays a role in vesicle maturation during exocytosis as a target of the diacylglycerol second messenger pathway.
EFHC1	EF-hand domain-containing protein 1	Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating.
PRICKLE1	Prickle-like protein 1	Involved in the planar cell polarity pathway that controls convergent extension during gastrulation and neural tube closure.
RBFOX1	RNA binding protein fox-1 homolog 1	RNA-binding protein that regulates alternative splicing events by binding to 5’-UGCAUGU-3’ elements.
CELSR1	Cadherin EGF LAG seven-pass G-type receptor 1	Receptor that may have an important role in cell/cell signaling during nervous system formation.
KCNH7	Voltage-gated inwardly rectifying potassium channel KCNH7	Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel.
ACMSD	2-amino-3-carboxymuconate-6-semialdehyde decarboxylase	Converts alpha-amino-beta-carboxymuconate-epsilon-semialdehyde (ACMS) to alpha-aminomuconate semialdehyde (AMS).
SV2A	Synaptic vesicle glycoprotein 2A	Plays a role in the control of regulated secretion in neural and endocrine cells, enhancing selectively low-frequency neurotransmission.
MICAL1	[F-actin]-monooxygenase MICAL1	Monooxygenase that promotes depolymerization of F-actin by mediating oxidation of specific methionine residues on actin to form methionine-sulfoxide, resulting in actin filament disassembly and preventing repolymerization.
SLITRK3	SLIT and NTRK-like protein 3	Suppresses neurite outgrowth.
CRH	Corticoliberin	Hormone regulating the release of corticotropin from pituitary gland.
SLC7A6OS	Probable RNA polymerase II nuclear localization protein SLC7A6OS	Directs RNA polymerase II nuclear import.
RBFOX3	RNA binding protein fox-1 homolog 3	Pre-mRNA alternative splicing regulator.
ADRA2B	Alpha-2B adrenergic receptor	Alpha-2 adrenergic receptors are G protein-coupled receptors for catecholamines that activate G(i/o) protein pathway, thereby promoting adenylyl cyclase inhibition, ERK1/2 stimulation, and voltage-gated calcium channels suppression.
CCDC22	Coiled-coil domain-containing protein 22	Component of the commander complex that is essential for endosomal recycling of transmembrane cargos; the Commander complex is composed of composed of the CCC subcomplex and the retriever subcomplex.
PLEKHG2	Pleckstrin homology domain-containing family G member 2	May be a transforming oncogene with exchange activity for CDC42.
SCAMP5	Secretory carrier-associated membrane protein 5	Required for the calcium-dependent exocytosis of signal sequence-containing cytokines such as CCL5.
GABRA6	Gamma-aminobutyric acid receptor subunit alpha-6	Alpha subunit of the heteropentameric ligand-gated chloride channel gated by gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain.
APBA2	Amyloid-beta A4 precursor protein-binding family A member 2	Putative function in synaptic vesicle exocytosis by binding to STXBP1, an essential component of the synaptic vesicle exocytotic machinery.
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.
KCNJ3	G protein-activated inward rectifier potassium channel 1	Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it.
ZFHX3	Zinc finger homeobox protein 3	Transcriptional regulator which can act as an activator or a repressor.
RORB	Nuclear receptor ROR-beta	Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5’-AGGTCA-3’ preceded by a short A-T-rich sequence.
RYR1	Ryanodine receptor 1	Cytosolic calcium-activated calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytosol and thereby plays a key role in triggering muscle contraction following depolarization of T-tubules.
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…
BRAP	BRCA1-associated protein	Negatively regulates MAP kinase activation by limiting the formation of Raf/MEK complexes probably by inactivation of the KSR1 scaffold protein.
SLC2A1	Solute carrier family 2, facilitated glucose transporter member 1	Facilitative glucose transporter, which is responsible for constitutive or basal glucose uptake.
SOX1	Transcription factor SOX-1	Transcriptional activator.
BTD	Biotinidase	Catalytic release of biotin from biocytin, the product of biotin-dependent carboxylases degradation.
SYN1	Synapsin-1	Neuronal phosphoprotein that coats synaptic vesicles, and binds to the cytoskeleton.
SYT2	Synaptotagmin-2	Exhibits calcium-dependent phospholipid and inositol polyphosphate binding properties.
TSC1	Hamartin	Non-catalytic component of the TSC-TBC complex, a multiprotein complex that acts as a negative regulator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolec…
TSC2	Tuberin	Catalytic component of the TSC-TBC complex, a multiprotein complex that acts as a negative regulator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule…
TSHR	Thyrotropin receptor	Receptor for the thyroid-stimulating hormone (TSH) or thyrotropin.
DNAJC7	DnaJ homolog subfamily C member 7	Acts as a co-chaperone regulating the molecular chaperones HSP70 and HSP90 in folding of steroid receptors, such as the glucocorticoid receptor and the progesterone receptor.
ACR	Acrosin	Acrosin is the major protease of mammalian spermatozoa.
WWOX	WW domain-containing oxidoreductase	Putative oxidoreductase.
BCL11A	BCL11 transcription factor A	Transcription factor.
ATP8A2	Phospholipid-transporting ATPase IB	Catalytic component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of aminophospholipids from the outer to the inner leaflet of various membranes and ensures the maintenance of asymmetric dis…
FRRS1L	DOMON domain-containing protein FRRS1L	Important modulator of glutamate signaling pathway.
CYFIP1	Cytoplasmic FMR1-interacting protein 1	Component of the CYFIP1-EIF4E-FMR1 complex which binds to the mRNA cap and mediates translational repression.

Protein-family classification

Druggable: 25 · Difficult: 20 · Unknown: 30 · Druggable fraction: 0.33

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Ion channel	12	17.9×	3e-11
Nuclear receptor	1	5.2×	0.399
Scaffold/PPI	7	1.6×	0.399
Transcription factor	13	1.4×	0.399
Transporter	2	2.1×	0.452
Protease	2	1.0×	0.786
GPCR	3	1.0×	0.786
Enzyme (other)	5	0.8×	0.855
Other/Unknown	30	0.7×	0.998

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCN1A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a1su
SCN2A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
SCN3A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_trans_assoc_dom
SCN9A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
BSN	Transcription factor	no		Znf_piccolo, Znf_FYVE_PHD, Znf_RING/FYVE/PHD
TTC21B	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, TTC21A/TTC21B
AGBL2	Protease	yes		Peptidase_M14, Pepdidase_M14_N, Cytosolic_carboxypeptidase
GABRG2	Other/Unknown	no		GABRG-1/4, GABBAg2_rcpt, GABAA/Glycine_rcpt
SEC24D	Transcription factor	no		Znf_Sec23_Sec24, Sec23/24_trunk_dom, Sec23/24_helical_dom
UNC13B	Other/Unknown	no		C2_dom, PKC_DAG/PE, MUN_dom
EFHC1	Other/Unknown	no		EF_hand_dom, DM10_dom, EF-hand-dom_pair
PRICKLE1	Transcription factor	no		Znf_LIM, PET_domain, PET_prickle
RBFOX1	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, RBFOX1-3
CELSR1	GPCR	yes		EGF-type_Asp/Asn_hydroxyl_site, GPS, EGF
KCNH7	Ion channel	yes		PAS, cNMP-bd_dom, K_chnl_volt-dep_EAG/ELK/ERG
ACMSD	Enzyme (other)	yes	4.1.1.45	Amidohydro-rel, ACMSD, Metal_Hydrolase
SV2A	Transporter	yes		MFS_sugar_transport-like, Sugar_transporter_CS, MFS
MICAL1	Transcription factor	no	1.14.13.225	CH_dom, Znf_LIM, FAD-bd
SLITRK3	Other/Unknown	no		Cys-rich_flank_reg_C, Leu-rich_rpt, Leu-rich_rpt_typical-subtyp
CRH	Other/Unknown	no		CRF, Urocortin_CRF, Corticotropin-releasing_fac_CS
SLC7A6OS	Transcription factor	no		TF_Iwr1_dom, SLC7A6OS
RBFOX3	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, RBFOX1-3
ADRA2B	GPCR	yes		ADRA2B_rcpt, GPCR_Rhodpsn, ADR_fam
CCDC22	Other/Unknown	no		CCDC22, CCDC22_CC, CCDC22_N
PLEKHG2	Scaffold/PPI	no		DH_dom, PH_domain, PH-like_dom_sf
SCAMP5	Other/Unknown	no		SCAMP
GABRA6	Other/Unknown	no		GABAAa_rcpt, GABBAa6_rcpt, GABAA/Glycine_rcpt
APBA2	Scaffold/PPI	no		PDZ, PTB/PI_dom, PH-like_dom_sf
KCNA1	Ion channel	yes		BTB/POZ_dom, T1-type_BTB, K_chnl_volt-dep_Kv
KCNJ3	Ion channel	yes		K_chnl_inward-rec_Kir3.1, K_chnl_inward-rec_Kir_cyto, Ig_E-set
ZFHX3	Transcription factor	no		HD, Matrin/U1-like-C_Znf_C2H2, Homeodomain-like_sf
RORB	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
RYR1	Ion channel	yes		RIH_dom, B30.2/SPRY, Ryanodine_rcpt
SCN8A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
BRAP	Transcription factor	no		Znf_UBP, Znf_RING, BRAP2/ETP1_RRM
SLC2A1	Transporter	yes		Glu_transpt_1, Sugar/inositol_transpt, MFS_sugar_transport-like
SOX1	Transcription factor	no		HMG_box_dom, SOX_fam, HMG_box_dom_sf
BTD	Enzyme (other)	yes	3.5.1.12	C-N_Hydrolase, Biotinidase-like_euk, C-N_Hydrolase_sf
SYN1	Other/Unknown	no		Synapsin, ATP_grasp_subdomain_1, PreATP-grasp_dom_sf
SYT2	Other/Unknown	no		C2_dom, Synaptotagmin, C2_domain_sf
TSC1	Other/Unknown	no		Hamartin
TSC2	Other/Unknown	no		Rap/Ran_GAP_dom, Tuberin, ARM-like
TSHR	GPCR	yes		GPCR_Rhodpsn, Gphrmn_rcpt_fam, TSH_rcpt
DNAJC7	Other/Unknown	no		DnaJ_domain, TPR-like_helical_dom_sf, TPR_rpt
ACR	Protease	yes	3.4.21.10	Trypsin_dom, Peptidase_S1A, Peptidase_S1_PA
WWOX	Scaffold/PPI	no		WW_dom, SDR_fam, WW_dom_sf
BCL11A	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Dev/Hematopoietic_TF
ATP8A2	Transcription factor	no	7.6.2.1	P_typ_ATPase, P-type_ATPase_IV, ATPase_P-typ_transduc_dom_A_sf
FRRS1L	Other/Unknown	no		DOMON_domain, FRRS1L
MACF1	Scaffold/PPI	no		Spectrin_repeat, EF_hand_dom, GAR_dom

Expression context

Cohort genes with no expression data: 0.

66 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)	75
unknown	0

Top tissues across cohort

Tissue	Cohort genes
middle temporal gyrus	13
Brodmann (1909) area 23	10
right hemisphere of cerebellum	8
sural nerve	7
lateral nuclear group of thalamus	6
cerebellar hemisphere	6
cortical plate	5
ventricular zone	5
apex of heart	5
cerebellar cortex	5
endothelial cell	4
stromal cell of endometrium	4
right uterine tube	4
tendon of biceps brachii	4
right lobe of liver	4
granulocyte	4
prefrontal cortex	4
ganglionic eminence	4
primary visual cortex	3
cerebellar vermis	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCN1A	154	tissue_specific	marker	Brodmann (1909) area 23, lateral nuclear group of thalamus, primary visual cortex
SCN2A	187	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, cerebellar vermis
SCN3A	221	broad	marker	endothelial cell, cortical plate, middle temporal gyrus
SCN9A	187	ubiquitous	marker	sural nerve, dorsal root ganglion, stromal cell of endometrium
BSN	156	broad	marker	frontal pole, paraflocculus, middle temporal gyrus
TTC21B	179	ubiquitous	marker	right uterine tube, calcaneal tendon, cerebellar hemisphere
AGBL2	133	ubiquitous	marker	right uterine tube, left testis, right testis
GABRG2	174	tissue_specific	marker	middle temporal gyrus, Brodmann (1909) area 23, superior frontal gyrus
SEC24D	263	ubiquitous	marker	stromal cell of endometrium, jejunal mucosa, islet of Langerhans
UNC13B	287	ubiquitous	marker	right lung, pancreatic ductal cell, lower lobe of lung
EFHC1	272	ubiquitous	marker	bronchial epithelial cell, epithelium of bronchus, bronchus
PRICKLE1	243	ubiquitous	marker	buccal mucosa cell, tendon of biceps brachii, lateral nuclear group of thalamus
RBFOX1	220	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, cortical plate
CELSR1	224	ubiquitous	marker	ventricular zone, lower esophagus mucosa, bronchial epithelial cell
KCNH7	90	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, pancreatic ductal cell, ventricular zone
ACMSD	151	tissue_specific	marker	kidney epithelium, right lobe of liver, liver
SV2A	220	ubiquitous	marker	Brodmann (1909) area 10, lateral nuclear group of thalamus, paraflocculus
MICAL1	234	ubiquitous	marker	right coronary artery, granulocyte, left coronary artery
SLITRK3	151	tissue_specific	yes	left uterine tube, middle temporal gyrus, prefrontal cortex
CRH	97	tissue_specific	marker	lateral nuclear group of thalamus, placenta, buccal mucosa cell
SLC7A6OS	224	ubiquitous	yes	pancreatic ductal cell, tendon of biceps brachii, apex of heart
RBFOX3	177	broad	marker	right hemisphere of cerebellum, cerebellar cortex, cerebellar hemisphere
ADRA2B	147	broad	marker	apex of heart, tendon of biceps brachii, gastrocnemius
CCDC22	258	ubiquitous	yes	granulocyte, monocyte, leukocyte
PLEKHG2	178	ubiquitous	marker	sural nerve, descending thoracic aorta, right coronary artery
SCAMP5	217	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
GABRA6	105	tissue_specific	marker	cerebellar vermis, cerebellar cortex, cerebellar hemisphere
APBA2	131	ubiquitous	marker	superior frontal gyrus, right hemisphere of cerebellum, cerebellum
KCNA1	151	broad	marker	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus
KCNJ3	196	broad	marker	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus

Protein interactions among cohort

Intra-cohort edges: 45.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
WWOX	5,892
SLC2A1	5,711
TSC1	5,445
RBFOX3	4,442
TSC2	4,135
DNAJC7	4,096
CAD	3,613
ZEB2	3,193
SYN1	3,188
KCNA1	3,157

Intra-cohort edges

A	B	Sources
ADRA2B	SEC24D	string_interaction
APBA2	SCAMP5	string_interaction
ARHGEF9	CRAMP1	intact
ARHGEF9	PCDH19	string_interaction
ATP8A2	CACNA1C	intact
BCL11A	TSC1	intact
BRAP	EFHC1	biogrid_interaction, intact
CACNA1A	CACNB4	biogrid_interaction
CACNA1C	CACNB4	intact
CACNA1C	SCN2A	intact
CACNA1C	SCN3A	intact
CACNA1C	SCN9A	intact
CACNA1C	SLITRK3	intact
CACNB4	EFHC1	string_interaction
CACNB4	KCNA1	string_interaction
CAD	DNAJC7	biogrid_interaction
CELSR1	PRICKLE1	string_interaction
CNTNAP2	KCNA1	string_interaction
CNTNAP2	MACF1	biogrid_interaction
CRAMP1	JPT2	string_interaction
EFHC1	SCN1A	string_interaction
GABRA6	SCN1A	string_interaction
GABRG2	PCDH19	string_interaction
GABRG2	SCN1A	string_interaction
GABRG2	SCN2A	string_interaction
GABRG2	SCN8A	string_interaction
GABRG2	SCN9A	string_interaction
JPT2	RYR1	string_interaction
KCNA1	SCN2A	string_interaction
KCNA1	SCN8A	string_interaction
KCNH7	KCNJ3	string_interaction
PCDH19	SCN1A	string_interaction
PCDH19	SCN2A	string_interaction
RBFOX1	RBFOX3	biogrid_interaction
RPH3A	UNC13B	string_interaction
SCAMP5	SV2A	string_interaction
SCN1A	SCN2A	biogrid_interaction, string_interaction
SCN2A	SCN3A	intact
SCN2A	SCN9A	intact
SV2A	SYN1	string_interaction
SV2A	SYT2	string_interaction
SV2A	TTC21B	intact
SYN1	SYT2	string_interaction
SYT2	UNC13B	string_interaction
TSC1	TSC2	biogrid_interaction, intact, string_interaction

Structural data

PDB: 46 · AlphaFold-only: 29 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GABRG2	P18507	75
CAD	P27708	55
SCN9A	Q15858	43
CACNA1C	Q13936	33
SV2A	Q7L0J3	23
BCL11A	Q9H165	17
MICAL1	Q8TDZ2	11
BRD7	Q9NPI1	11
APTX	Q7Z2E3	11
SRCAP	Q6ZRS2	10
TSHR	P16473	9
SCN8A	Q9UQD0	7
SEC24D	O94855	6
ACMSD	Q8TDX5	6
CBX1	P83916	6
SCN2A	Q99250	5
CRH	P06850	5
SLC2A1	P11166	5
TSC1	Q92574	5
CYFIP1	Q7L576	5
SNX11	Q9Y5W9	5
CHCHD10	Q8WYQ3	5
RBFOX1	Q9NWB1	4
CCDC22	O60826	4
CACNA1A	O00555	4
TTC21B	Q7Z4L5	3
ZFHX3	Q15911	3
MACF1	O94854	3
SCN3A	Q9NY46	2
EFHC1	Q5JVL4	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DNAJC7	Q99615	90.83
BTD	P43251	86.77
SCAMP5	Q8TAC9	86.48
GABRA6	Q16445	82.69
ATP8A2	Q9NTI2	81.12
FRRS1L	Q9P0K9	80.60
ACR	P10323	80.10
RORB	Q92753	79.48
KCNA1	Q09470	78.74
ARHGAP11B	Q3KRB8	77.88
BRAP	Q7Z569	76.92
UNC13B	O14795	75.85
KCNJ3	P48549	72.88
AGBL2	Q5U5Z8	72.22
TMEM204	Q9BSN7	70.99
SYN1	P17600	69.86
RPH3A	Q9Y2J0	69.79
GOLIM4	O00461	68.20
SLC7A6OS	Q96CW6	66.54
SLITRK3	O94933	64.70
PIGQ	Q9BRB3	64.70
RBFOX3	A6NFN3	62.27
JPT2	Q9H910	60.42
APBA2	Q99767	59.74
SOX1	O00570	59.29
PRICKLE1	Q96MT3	55.55
CRAMP1	Q96RY5	50.96
PLEKHG2	Q9H7P9	48.39
BSN	Q9UPA5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 461. Enrichment computed across 201 evidence-associated genes (143 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 143 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Neuronal System	19	5.9×	2e-07	SYN1, SYT2, CACNA1A, CACNB4, ARHGEF9, KCNH7, CHRNA1, CHRNA2 (+11 more)
GABA receptor activation	7	15.5×	5e-05	GABRG2, ARHGEF9, GABRA1, GABRA2, GABRA6, GABRB3, KCNJ3
Muscle contraction	12	6.5×	5e-05	SCN1A, SCN2A, SCN3A, SCN9A, RYR1, SCN8A, CACNA1C, CACNA1G (+4 more)
Cardiac conduction	10	7.6×	8e-05	SCN1A, SCN2A, SCN3A, SCN9A, RYR1, SCN8A, CACNA1C, KCND3 (+2 more)
Interaction between L1 and Ankyrins	6	15.5×	2e-04	SCN1A, SCN2A, SCN3A, SCN9A, SCN8A, KCNQ2
Phase 0 - rapid depolarisation	6	14.5×	2e-04	SCN1A, SCN2A, SCN3A, SCN9A, SCN8A, CACNA1C
MECP2 regulates transcription factors	3	47.9×	0.001	RBFOX1, MECP2, MEF2C
Transmission across Chemical Synapses	10	5.3×	0.001	SYN1, CACNA1A, CACNB4, ARHGEF9, CHRNA1, CHRNA2, CHRNA7, ALDH2 (+2 more)
Voltage gated Potassium channels	6	10.2×	0.001	KCNH7, KCNA1, KCNB1, KCND3, KCNH1, KCNQ2
Neurexins and neuroligins	6	8.3×	0.004	SYT2, DLG3, GRIN2A, GRIN2B, APBA2, NRXN2
Potassium Channels	7	6.6×	0.004	KCNH7, KCNA1, KCNB1, KCND3, KCNH1, KCNJ3, KCNQ2
Synaptic adhesion-like molecules	4	15.2×	0.005	DLG3, GRIN2A, GRIN2B, PTPRD
Highly calcium permeable postsynaptic nicotinic acetylcholine receptors	3	21.8×	0.010	CHRNA1, CHRNA2, CHRNA7
Regulation of insulin secretion	5	7.7×	0.015	SLC2A1, CACNA1A, CACNA1C, CHRM3, KCNB1
Acetylcholine binding and downstream events	3	17.1×	0.018	CHRNA1, CHRNA2, CHRNA7
Postsynaptic nicotinic acetylcholine receptors	3	17.1×	0.018	CHRNA1, CHRNA2, CHRNA7
Respiratory electron transport	7	4.7×	0.021	MT-CO1, MT-CO2, MT-CO3, MT-CYB, MT-ND2, MT-ND4, NDUFV2
L1CAM interactions	6	5.0×	0.031	SCN1A, SCN2A, SCN3A, SCN9A, SCN8A, KCNQ2
Inhibition of TSC complex formation by AKT (PKB)	2	31.9×	0.037	TSC1, TSC2
MECP2 regulates neuronal receptors and channels	3	12.6×	0.037	GRIN2A, GRIN2B, MECP2
Mitochondrial translation termination	6	4.6×	0.042	MT-CO1, MT-CO2, MT-CO3, MT-CYB, MT-ND2, MT-ND4
Unblocking of NMDA receptors, glutamate binding and activation	3	11.4×	0.043	DLG3, GRIN2A, GRIN2B
Negative regulation of NMDA receptor-mediated neuronal transmission	3	11.4×	0.043	DLG3, GRIN2A, GRIN2B
Assembly and cell surface presentation of NMDA receptors	4	7.1×	0.045	DLG3, GRIN2A, GRIN2B, NBEA
NCAM1 interactions	4	6.9×	0.047	CACNA1C, CACNA1G, CACNB4, GFRA1
Neurotransmitter receptors and postsynaptic signal transmission	6	4.2×	0.054	ARHGEF9, CHRNA1, CHRNA2, CHRNA7, KCNJ3, NBEA
Long-term potentiation	3	10.0×	0.055	DLG3, GRIN2A, GRIN2B
Neurotoxicity of clostridium toxins	2	20.0×	0.066	SYT2, SV2A
MECP2 regulates transcription of neuronal ligands	2	20.0×	0.066	CRH, MECP2
Axon guidance	9	2.8×	0.069	SCN1A, SCN2A, SCN3A, SCN9A, SCN8A, CACNA1C, CACNA1G, CACNB4 (+1 more)

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 183 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
chemical synaptic transmission	18	7.6×	4e-08	BSN, SYN1, UNC13B, CACNA1A, CACNA1G, CACNB4, CHRM3, CHRNA7 (+10 more)
cardiac muscle cell action potential involved in contraction	7	26.9×	3e-06	SCN1A, SCN2A, SCN3A, SCN9A, SCN8A, CACNA1C, CACNA1G
gamma-aminobutyric acid signaling pathway	6	17.8×	3e-04	GABRG2, CACNB4, GABRA1, GABRA2, GABRA6, GABRB3
positive regulation of excitatory postsynaptic potential	6	17.3×	3e-04	CUX2, CHRNA7, TBC1D24, GRIN2A, GRIN2B, RELN
regulation of membrane potential	8	10.1×	3e-04	CACNA1G, KCNH7, CHRNA1, CHRNA7, HCN1, ABCC1, KCNA1, KCNH1
potassium ion transmembrane transport	10	7.4×	3e-04	KCNH7, KCNT1, HCN1, KCNA1, KCNB1, KCND3, KCNH1, KCNJ3 (+2 more)
synaptic transmission, GABAergic	6	16.2×	3e-04	GABRG2, SLITRK3, GABRA1, GABRA2, GABRA6, GABRB3
neuronal action potential	6	15.8×	3e-04	SCN1A, SCN2A, SCN9A, CHRNA1, HCN1, KCNA1
nervous system development	16	4.0×	4e-04	SCN2A, ZEB2, ARID1B, RBFOX1, CHRM3, RBFOX3, DLG3, GFRA1 (+8 more)
sodium ion transmembrane transport	8	8.9×	4e-04	SCN1A, SCN2A, SCN3A, SCN9A, SCN8A, GRIN2A, HCN1, ATP1A2
response to hypoxia	11	5.8×	4e-04	RYR1, SLC2A1, CHRNA7, ABCB1, MECP2, MT-CO1, MT-CO2, MT-CYB (+3 more)
inhibitory synapse assembly	5	17.1×	0.001	GABRG2, GABRA1, GABRA2, GABRA6, GABRB3
cellular response to histamine	3	46.0×	0.002	GABRG2, DIAPH1, GABRB3
female pregnancy	7	8.1×	0.002	SLC2A1, CAD, CORIN, CRH, ADRA2B, ABCB1, LGALS9
response to glycoside	3	39.5×	0.004	ABCB1, ATP1A2, ATP1A3
vocalization behavior	4	19.4×	0.004	CNTNAP2, SRPX2, NRXN2, NTSR1
excitatory postsynaptic potential	5	12.1×	0.004	CHRNA7, GRIN2A, GRIN2B, MECP2, MEF2C
response to nicotine	5	11.5×	0.005	CHRNA1, CHRNA2, CHRNA7, MT-ND4, ATP1A2
central nervous system projection neuron axonogenesis	3	30.7×	0.007	KIFBP, EPHB1, NR4A2
ceramide translocation	2	92.1×	0.008	ABCA2, ABCB1
regulation of heart rate by cardiac conduction	5	10.2×	0.008	CACNA1C, CACNA1G, HCN1, KCND3, KCNJ3
action potential	5	9.8×	0.009	SCN8A, KCNA1, KCNB1, KCND3, KCNQ2
acetylcholine receptor signaling pathway	4	13.6×	0.011	CHRM3, CHRNA1, CHRNA2, CHRNA7
neuronal action potential propagation	3	23.0×	0.013	SCN1A, CACNB4, ATP1A2
cell communication by electrical coupling involved in cardiac conduction	3	23.0×	0.013	CACNA1C, ATP1A2, ATP1A3
response to ethanol	7	5.6×	0.013	CLDN5, CRH, GRIN2A, GRIN2B, MT-CO2, MT-CYB, MT-ND4
ventricular cardiac muscle cell membrane repolarization	2	61.4×	0.016	KCND3, KCNJ3
positive regulation of calcium ion-dependent exocytosis	3	21.2×	0.016	RPH3A, SCAMP5, KCNB1
adult locomotory behavior	5	8.2×	0.016	TSC1, MECP2, NR4A2, ATP1A2, NTSR1
potassium ion transport	6	6.3×	0.018	TSC1, KCNH7, KCND3, KCNH1, KCNJ3, ATP1A2

Therapeutics

Drugs indicated for this disease

44 approved, 17 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Acetazolamide	Approved (phase 4)
Barbexaclone	Approved (phase 4)
Brivaracetam	Approved (phase 4)
Cannabidiol	Approved (phase 4)
Carbamazepine	Approved (phase 4)
Cenobamate	Approved (phase 4)
Clonazepam	Approved (phase 4)
Diazepam	Approved (phase 4)
Eslicarbazepine	Approved (phase 4)
Eslicarbazepine Acetate	Approved (phase 4)
Ethosuximide	Approved (phase 4)
Ethotoin	Approved (phase 4)
Ezogabine	Approved (phase 4)
Felbamate	Approved (phase 4)
Fenfluramine	Approved (phase 4)
Fosphenytoin	Approved (phase 4)
Gabapentin	Approved (phase 4)
Ganaxolone	Approved (phase 4)
Lacosamide	Approved (phase 4)
Lamotrigine	Approved (phase 4)
Levetiracetam	Approved (phase 4)
Mephenytoin	Approved (phase 4)
Mephobarbital	Approved (phase 4)
Metharbital	Approved (phase 4)
Methsuximide	Approved (phase 4)
Midazolam	Approved (phase 4)
Oxcarbazepine	Approved (phase 4)
Paramethadione	Approved (phase 4)
Perampanel	Approved (phase 4)
Phenacemide	Approved (phase 4)
Phenobarbital	Approved (phase 4)
Phensuximide	Approved (phase 4)
Phenytoin	Approved (phase 4)
Pregabalin	Approved (phase 4)
Primidone	Approved (phase 4)
Rufinamide	Approved (phase 4)
Stiripentol	Approved (phase 4)
Sulthiame	Approved (phase 4)
Tiagabine	Approved (phase 4)
Topiramate	Approved (phase 4)
Trimethadione	Approved (phase 4)
Valproic Acid	Approved (phase 4)
Vigabatrin	Approved (phase 4)
Zonisamide	Approved (phase 4)
Cannabinol	Phase 3 (in late-stage trials)
Carisbamate	Phase 3 (in late-stage trials)
Cholecalciferol	Phase 3 (in late-stage trials)
Dextrose	Phase 3 (in late-stage trials)
Folic Acid	Phase 3 (in late-stage trials)
Human Immunoglobulin G	Phase 3 (in late-stage trials)
Ketamine	Phase 3 (in late-stage trials)
Lemborexant	Phase 3 (in late-stage trials)
Lorazepam	Phase 3 (in late-stage trials)
Metformin	Phase 3 (in late-stage trials)
Naloxone	Phase 3 (in late-stage trials)
Progesterone	Phase 3 (in late-stage trials)
Saccharin	Phase 3 (in late-stage trials)
Seletracetam	Phase 3 (in late-stage trials)
Sodium Chloride	Phase 3 (in late-stage trials)
TECHNETIUM TC 99M TILMANOCEPT	Phase 3 (in late-stage trials)
Tocilizumab	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Acetylcysteine, Alprazolam, Ascorbic Acid, Ataluren, Carvedilol, Clioquinol, Clobazam, Corn Oil, Corticotropin, Everolimus, Fish Oil, Fluoxetine, Ibuprofen, Icosapent, Lactobacillus Acidophilus, Melatonin, Nifedipine, Nitrazepam, OMEGA-3 FATTY ACIDS, OMEGA-3-ACID ETHYL ESTERS, Pentoxifylline, Pyridoxine.

Drug target analysis

Approved (phase 4): 19 · Phase ≥3: 19 · Phased (≥1): 20 · Undrugged: 55

Druggability breadth: 101 of 201 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SCN1A	MEXILETINE HYDROCHLORIDE
SCN2A	BEPRIDIL
SCN3A	BEPRIDIL
SCN9A	IMIPRAMINE
GABRG2	ENZALUTAMIDE
ACMSD	DIFLUNISAL
ADRA2B	BEPRIDIL
GABRA6	ENZALUTAMIDE
KCNA1	NIFEDIPINE
RORB	TRETINOIN
SCN8A	IMIPRAMINE
SLC2A1	EMETINE
TSHR	LEVOSALBUTAMOL
CACNA1A	NIMODIPINE
CACNA1C	REMIFENTANIL
CACNA1G	NIMODIPINE
CACNB4	NIMODIPINE
HDAC9	CELECOXIB
BRD7	SUNITINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TSHR	354	4
ADRA2B	316	4
SCN2A	99	4
SCN1A	94	4
SCN3A	93	4
CACNA1C	85	4
GABRG2	55	4
SCN9A	36	4
HDAC9	28	4
SCN8A	25	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MEXILETINE HYDROCHLORIDE	4	SCN1A, SCN9A
BEPRIDIL	4	ADRA2B, CACNA1C, SCN1A, SCN2A, SCN3A
DIBUCAINE	4	CACNA1C, SCN1A, SCN2A, SCN3A
ARTICAINE	4	SCN1A, SCN2A, SCN3A
BUPIVACAINE	4	SCN1A, SCN2A, SCN3A
IMIPRAMINE	4	ADRA2B, CACNA1C, SCN1A, SCN2A, SCN3A, SCN8A
DROPERIDOL	4	ADRA2B, CACNA1C, SCN1A, SCN2A, SCN3A
DICYCLOMINE	4	SCN1A, SCN2A, SCN3A, TSHR
TETRABENAZINE	4	SCN1A, SCN2A, SCN3A, TSHR
PHENIRAMINE	4	SCN1A, SCN2A, SCN3A
PRILOCAINE	4	SCN1A, SCN2A, SCN3A
PROPOXYCAINE	4	SCN1A, SCN2A, SCN3A
PROPARACAINE	4	SCN1A, SCN2A, SCN3A
HEXYLCAINE	4	SCN1A, SCN2A, SCN3A
PRAMOXINE	4	SCN1A, SCN2A, SCN3A
BENOXINATE	4	SCN1A, SCN2A, SCN3A, TSHR
QUINIDINE	4	ADRA2B, CACNA1C, SCN1A, SCN2A, SCN3A, TSHR
FELODIPINE	4	SCN1A, SCN2A, SCN3A
PHENYTOIN	4	CACNA1C, SCN1A, SCN2A, SCN3A
QUININE	4	SCN1A, SCN2A, SCN3A
NISOLDIPINE	4	CACNA1C, SCN1A, SCN2A, SCN3A
NIFEDIPINE	4	CACNA1C, KCNA1, SCN1A, SCN2A, SCN3A, SCN8A
PRAZOSIN	4	ADRA2B, SCN1A, SCN2A, SCN3A
DILTIAZEM	4	CACNA1C, SCN1A, SCN2A, SCN3A, SCN8A, SCN9A
PRENYLAMINE	4	ADRA2B, CACNA1C, SCN1A, SCN2A, SCN3A
COCAINE	4	SCN1A, SCN2A, SCN3A
TRIFLUOPERAZINE	4	ADRA2B, SCN1A, SCN2A, SCN3A, TSHR
CINNARIZINE	4	ADRA2B, SCN1A, SCN2A, SCN3A
THIORIDAZINE	4	ADRA2B, CACNA1C, SCN1A, SCN2A, SCN3A
ETIDOCAINE	4	SCN1A, SCN2A, SCN3A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 9.

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

Symbol	Assays	Type breakdown
HDAC9	1,625	Binding:1612, ADMET:8, Functional:4, Toxicity:1
GABRG2	1,155	Binding:940, Functional:201, ADMET:10, Toxicity:4
ADRA2B	596	Binding:466, Functional:123, ADMET:5, Unclassified:2
CACNA1C	575	Binding:319, Functional:211, Toxicity:26, ADMET:19
SCN9A	428	Binding:395, Functional:29, ADMET:3, Toxicity:1
GABRA6	264	Binding:227, Functional:33, Toxicity:3, ADMET:1
SCN2A	203	Binding:172, Functional:20, ADMET:10, Toxicity:1
SCN8A	173	Binding:148, Functional:16, ADMET:7, Toxicity:2
SLC2A1	158	Binding:130, ADMET:24, Functional:4
BRD7	152	Binding:146, ADMET:3, Functional:3
SCN1A	149	Binding:115, Functional:18, ADMET:14, Toxicity:2
CACNA1G	105	Binding:91, Functional:11, ADMET:2, Toxicity:1
SCN3A	102	Binding:79, Functional:18, ADMET:4, Toxicity:1
RORB	90	Binding:87, Functional:3
KCNA1	59	Binding:52, Functional:6, Toxicity:1
KCNJ3	53	Binding:53
TSHR	33	Functional:24, Binding:9
KCNH7	21	Binding:20, Toxicity:1
ACR	20	Binding:18, Functional:2
CACNA1A	19	Binding:18, Functional:1
ACMSD	18	Binding:18
CAD	17	Binding:16, ADMET:1
RYR1	16	Binding:13, Functional:3
CACNB4	13	Binding:13
DNAJC7	7	Binding:7
CYFIP1	7	Binding:7
CBX1	7	Binding:5, Functional:2
AGBL2	3	Binding:3
BTD	3	Binding:3
BRAP	2	Binding:2
SV2A	1	Binding:1
CRH	1	Binding:1
CCDC22	1	Binding:1
TSC2	1	Binding:1
JPT2	1	Binding:1
GOLIM4	1	Binding:1
APTX	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ACMSD	4.1.1.45	aminocarboxymuconate-semialdehyde decarboxylase
MICAL1	1.14.13.225	F-actin monooxygenase
BTD	3.5.1.12	biotinidase
ACR	3.4.21.10	acrosin
ATP8A2	7.6.2.1	P-type phospholipid transporter
HDAC9	3.5.1.98	histone deacetylase
PIGQ	2.4.1.198	phosphatidylinositol N-acetylglucosaminyltransferase
CAD	2.1.3.2, 3.5.2.3, 6.3.5.5	aspartate carbamoyltransferase, dihydroorotase, carbamoyl-phosphate synthase (glutamine-hydrolysing)
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

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN1A	149
SCN2A	203
SCN3A	102
SCN9A	428
GABRG2	1,155
ADRA2B	596
GABRA6	264
SCN8A	173
SLC2A1	158
CACNA1C	575
CACNA1G	105
HDAC9	1,625
BRD7	152

Pharmacogenomics

Cohort genes with a PharmGKB record: 74; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
RYR1	1

Chemical tractability of cohort targets

29 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)
MEXILETINE HYDROCHLORIDE	4	SCN1A, SCN9A
BEPRIDIL	4	ADRA2B, CACNA1C, SCN1A, SCN2A, SCN3A
DIBUCAINE	4	CACNA1C, SCN1A, SCN2A, SCN3A
ARTICAINE	4	SCN1A, SCN2A, SCN3A
BUPIVACAINE	4	SCN1A, SCN2A, SCN3A
IMIPRAMINE	4	ADRA2B, CACNA1C, SCN1A, SCN2A, SCN3A, SCN8A
DROPERIDOL	4	ADRA2B, CACNA1C, SCN1A, SCN2A, SCN3A
DICYCLOMINE	4	SCN1A, SCN2A, SCN3A, TSHR
TETRABENAZINE	4	SCN1A, SCN2A, SCN3A, TSHR
PHENIRAMINE	4	SCN1A, SCN2A, SCN3A
PRILOCAINE	4	SCN1A, SCN2A, SCN3A
PROPOXYCAINE	4	SCN1A, SCN2A, SCN3A
PROPARACAINE	4	SCN1A, SCN2A, SCN3A
HEXYLCAINE	4	SCN1A, SCN2A, SCN3A
PRAMOXINE	4	SCN1A, SCN2A, SCN3A
BENOXINATE	4	SCN1A, SCN2A, SCN3A, TSHR
QUINIDINE	4	ADRA2B, CACNA1C, SCN1A, SCN2A, SCN3A, TSHR
FELODIPINE	4	SCN1A, SCN2A, SCN3A
QUININE	4	SCN1A, SCN2A, SCN3A
NISOLDIPINE	4	CACNA1C, SCN1A, SCN2A, SCN3A
NIFEDIPINE	4	CACNA1C, KCNA1, SCN1A, SCN2A, SCN3A, SCN8A
PRAZOSIN	4	ADRA2B, SCN1A, SCN2A, SCN3A
DILTIAZEM	4	CACNA1C, SCN1A, SCN2A, SCN3A, SCN8A, SCN9A
PRENYLAMINE	4	ADRA2B, CACNA1C, SCN1A, SCN2A, SCN3A
COCAINE	4	SCN1A, SCN2A, SCN3A
TRIFLUOPERAZINE	4	ADRA2B, SCN1A, SCN2A, SCN3A, TSHR
CINNARIZINE	4	ADRA2B, SCN1A, SCN2A, SCN3A
THIORIDAZINE	4	ADRA2B, CACNA1C, SCN1A, SCN2A, SCN3A
ETIDOCAINE	4	SCN1A, SCN2A, SCN3A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	19	SCN1A, SCN2A, SCN3A, SCN9A, GABRG2, ACMSD, ADRA2B, GABRA6, KCNA1, RORB (+9 more)
B	Phased (≥1) drug, not yet approved	1	DNAJC7
C	Druggable family + PDB, no drug	5	CELSR1, KCNH7, SV2A, RYR1, CAD
D	Druggable family + AlphaFold only, no drug	5	AGBL2, KCNJ3, BTD, ACR, PIGQ
E	Difficult family or no structure, no drug	45	BSN, TTC21B, SEC24D, UNC13B, EFHC1, PRICKLE1, RBFOX1, MICAL1, SLITRK3, CRH (+35 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
EFHC1	0	CACNB4
CNTNAP2	0	KCNA1
PCDH19	0	SCN1A
BSN	0	—
TTC21B	0	—
AGBL2	3	—
SEC24D	0	—
UNC13B	0	—
PRICKLE1	0	—
RBFOX1	0	—
CELSR1	0	—
KCNH7	21	—
SV2A	1	—
MICAL1	0	—
SLITRK3	0	—
CRH	1	—
SLC7A6OS	0	—
RBFOX3	0	—
CCDC22	1	—
PLEKHG2	0	—
SCAMP5	0	—
APBA2	0	—
KCNJ3	53	—
ZFHX3	0	—
RYR1	16	—
BRAP	2	—
SOX1	0	—
BTD	3	—
SYN1	0	—
SYT2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1,421.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	580
PHASE3	161
PHASE2	121
PHASE1	100
PHASE4	96
PHASE1/PHASE2	17
EARLY_PHASE1	15
PHASE2/PHASE3	10

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02670161	PHASE4	ENROLLING_BY_INVITATION	Quality Improvement and Practice Based Research in Neurology Using the EMR
NCT04144439	PHASE4	RECRUITING	Effect of GABA on ADHD and Seizures in Children With Epilepsy.
NCT04419272	PHASE4	RECRUITING	Methylphenidate for the Treatment of Epilepsy-related Cognitive Deficits
NCT05881928	PHASE4	NOT_YET_RECRUITING	Effect of Adding Lamotrigine to Sodium Valproate in Childhood Epilepsy: Clinicolabratory Study
NCT06346262	PHASE4	RECRUITING	Seizure Rescue Medication (RM) as Part of a Comprehensive Epilepsy Self-management Package of Care
NCT06534502	PHASE4	NOT_YET_RECRUITING	Study of the Pharmacokinetics, Safety, and Tolerability of ZONISADE in Children 1 Month to 17 Years of Age With Partial-onset Seizures
NCT07046676	PHASE4	RECRUITING	Pharmacogenetics-Based Study on Individualized Use of Sodium Valproate
NCT00004637	PHASE4	COMPLETED	Double-Blind, Placebo-Controlled Trial of Vitamin E as Add-on Therapy for Children With Epilepsy
NCT00043914	PHASE4	COMPLETED	Measurement Of Serum Levels Of Two Antiepileptic Drugs During Conversion In Patients With Epilepsy
NCT00132223	PHASE4	UNKNOWN	Effects on the Diagnostic Accuracy of Magnetic Imaging Angiographies of the Supra-Aortic Vessels by Three Different Magnetic Resonance Contrast Agents in Patients
NCT00133081	PHASE4	UNKNOWN	Study to Improve the Treatment of Epilepsy (SITE)
NCT00137709	PHASE4	UNKNOWN	Hormone Profiles in Adults With Newly Diagnosed Epilepsy
NCT00154076	PHASE4	COMPLETED	A Multicenter Comparative Trial of Zonisamide and Topiramate as Initial Monotherapy in Untreated Epilepsies
NCT00165828	PHASE4	TERMINATED	Efficacy and Safety of an add-on Treatment With Zonisamide in Adults With Focal Epileptic Seizures With or Without Secondary Generalization
NCT00181116	PHASE4	COMPLETED	Levetiracetam for Benign Rolandic Epilepsy
NCT00207935	PHASE4	COMPLETED	Use of Sustained Release Antiepileptic Medication (Depakote® ER) for Pediatric Epilepsy in a Mental Retardation/Developmental Disorder Population
NCT00215592	PHASE4	COMPLETED	Open Label, Zonegran (Zonisamide) In Partial Onset Seizures
NCT00266604	PHASE4	COMPLETED	A Study to Evaluate the Dosing, Effectiveness and Safety of Topiramate for the Treatment of Epilepsy
NCT00288639	PHASE4	COMPLETED	Lyrica (Pregabalin) Administered as an Add-on Therapy for Partial Seizures (LEADER).
NCT00312676	PHASE4	UNKNOWN	Compare Tolerability of an Overnight Switch to Gradual Switch Between Two Different Forms of Depakote
NCT00323947	PHASE4	COMPLETED	Methylphenidate for Treating Attention Deficit Hyperactivity Disorder in Children With Both ADHD and Epilepsy
NCT00385411	PHASE4	COMPLETED	Study of Valproate in Young Patients Suffering From Epilepsy
NCT00522418	PHASE4	TERMINATED	Study Comparing Best Medical Practice With or Without VNS Therapy in Pharmacoresistant Partial Epilepsy Patients
NCT00537940	PHASE4	COMPLETED	Comparative Study Of Pregabalin And Gabapentin As Adjunctive Therapy In Subjects With Partial Seizures
NCT00552526	PHASE4	UNKNOWN	Ketogenic Diet vs.Antiepileptic Drug Treatment in Drug Resistant Epilepsy
NCT00564915	PHASE4	COMPLETED	RCT of the Efficacy of the Ketogenic Diet in the Treatment of Epilepsy
NCT00571155	PHASE4	COMPLETED	Trial of Levetiracetam in Patients With Primary Brain Tumors and Symptomatic Seizures Who Undergo Surgery
NCT00572195	PHASE4	COMPLETED	RNS® System LTT Study
NCT00610532	PHASE4	TERMINATED	Evaluating the Transporter Protein Inhibitor Probenecid In Patients With Epilepsy
NCT00630357	PHASE4	COMPLETED	Trial to Evaluate the Safety and Efficacy of Keppra After Conversion to Mono-therapy in Subjects With Partial Epilepsy
NCT00630630	PHASE4	COMPLETED	Study on Safety and Efficacy of Levetiracetam in the Adjunctive Treatment of Female Subjects With C1 Catamenial Epilepsy
NCT00630968	PHASE4	COMPLETED	S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00631150	PHASE4	COMPLETED	A Phase IV-Pharmacovigilance Study of Keppra Greece - S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00659958	PHASE4	COMPLETED	ZAGAL Study: Evaluating Effectiveness and Tolerability of Zonisamide as Adjunctive Therapy in Patients With Partial Onset Seizures Treated With Two Antiepileptic Drugs
NCT00713622	PHASE4	COMPLETED	Comparing The Effect On Cognition Of Adjunctive Therapy With Zonisamide Versus Sodium Valproate
NCT00807989	PHASE4	COMPLETED	The Efficacy and Safety of Low Dose Combination of LTG and VPA Compared to CBZ Monotherapy
NCT00832884	PHASE4	COMPLETED	The Safety of Intravenous Lacosamide
NCT00869622	PHASE4	COMPLETED	Antiepileptic Drugs and Osteoporotic Prevention Trial
NCT00896987	PHASE4	COMPLETED	Lamotrigine Cognitive Function Study in Adult Untreated Epilepsies
NCT00952081	PHASE4	COMPLETED	A Pilot Study to Evaluate Efficacy and Safety of Clevidipine in Neurosurgical Patients

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
LACOSAMIDE	4	37
ESLICARBAZEPINE ACETATE	4	30
LEVETIRACETAM	4	30
BRIVARACETAM	4	27
VALPROIC ACID	4	26
PERAMPANEL	4	25
LAMOTRIGINE	4	23
PHENYTOIN	4	22
ZONISAMIDE	4	16
TOPIRAMATE	4	15
CARBAMAZEPINE	4	14
CANNABIDIOL	4	12
EZOGABINE	4	11
OXCARBAZEPINE	4	10
FLUPIRTINE	4	9
MIDAZOLAM	4	8
CLOBAZAM	4	7
PHENOBARBITAL	4	7
PYRIDOXINE	4	6
ESLICARBAZEPINE	4	5
LORAZEPAM	4	4
CLONAZEPAM	4	3
ALBENDAZOLE	4	2
ALPRAZOLAM	4	2
CENOBAMATE	4	2
DIAZEPAM	4	2
DIGOXIN	4	2
ETHOSUXIMIDE	4	2
FENFLURAMINE	4	2
FOSPHENYTOIN	4	2