Idiopathic generalized epilepsy

Summary

Idiopathic generalized epilepsy (MONDO:0005579) is a disease caused by SHROOM4 (GenCC Strong), with 37 cohort genes (61 GWAS associations across 8 studies) and 21 clinical trials. The dominant Reactome pathway is Interaction between L1 and Ankyrins (3 cohort genes). Top therapeutic interventions include levetiracetam, perampanel, and valproic acid.

At a glance

• Causal gene: SHROOM4 (GenCC Strong)
• Cohort genes: 37
• GWAS associations: 61
• ClinVar variants: 5,254
• Clinical trials: 21

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	idiopathic generalized epilepsy
Mondo ID	MONDO:0005579
EFO	EFO:0005917
MeSH	C562694
OMIM	600669
DOID	DOID:1827
SNOMED CT	19598007
UMLS	C0270850
MedGen	75725
Is cancer (heuristic)	no

Also known as: EIG · epilepsy, idiopathic generalized · generalized epilepsy · hereditary idiopathic generalized epilepsy · idiopathic generalised epilepsy · idiopathic generalized epilepsy · IGE

Data availability: 5,254 ClinVar variants · 61 GWAS associations (8 studies) · 1 GenCC gene-disease record · 186 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neurological disease › hereditary generalized epilepsy › idiopathic generalized epilepsy

Related subtypes (1): generalized epilepsy with febrile seizures plus

Subtypes (2): variable-age onset idiopathic generalized epilepsy syndrome, childhood-onset idiopathic generalized epilepsy syndrome

Genetics & variants

GWAS landscape

61 GWAS associations across 8 studies. Top hits map to 21 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs11688767	7e-21	EIF2S2P7 - ACTG1P22	A
rs2678901	1e-18	VRK2	A
rs11191156	4e-14	ARMH3	A
rs77876353	2e-12	ACTG1P22 - VRK2	A
rs4596374	3e-12	LINC01957 - TRIM36	T
rs2780103	4e-12	HNRNPK-AS1	T
rs7277479	9e-12	KRTAP21-1 - KRTAP8-2P	A
rs1402398	1e-11	ACTG1P22 - VRK2	G	6.79
rs62151809	1e-11	CAPZBP1 - LINC01965	T
rs12997934	4e-11	EIF2S2P7 - ACTG1P22	C
rs1463849	4e-11	PCDH7 - LINC02497	A
rs9861238	1e-10	RFC3P1 - STAC	A
rs6545674	2e-10	VRK2	A
rs2905552	2e-10	SPOCK1	C
rs2585398	2e-10	PER1	A
rs469999	3e-10	EPIC1 - MIR3201	A
rs75483641	5e-10	AP3D1	T
rs739431	5e-10	SLC38A3	A
rs13416557	7e-10	LINC01122	T
rs6721964	7e-10	NAB1 - GLS	A
rs2236951	1e-09	CACNA2D2	T
rs1044352	2e-09	PCDH7	T	5.98
rs68082256	2e-09	ATXN1-AS1 - STMND1	A	6.02
rs4807201	2e-09	AP3D1	T
rs16955463	2e-09	SKAP1	T
rs876793	3e-09	RYR2	T
rs7211143	3e-09	SKAP1 - Y_RNA	A
rs62014006	4e-09	RBFOX1	T
rs264980	5e-09	CAPZBP1 - LINC01965	T
rs114131287	5e-09	ACVRL1 - ACVR1B	A

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90271609	International League Against Epilepsy Consortium on Complex Epilepsies	2023	6,952	42,436	GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture.
GCST90271612	International League Against Epilepsy Consortium on Complex Epilepsies	2023	6,952	42,436	GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture.
GCST007353	International League Against Epilepsy Consortium on Complex Epilepsies	2018	3,708	24,218	Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies.
GCST90651780	Liu TY	2025	848	218,635	Diversity and longitudinal records: Genetic architecture of disease associations and polygenic risk in the Taiwanese Han population.
GCST90053845	Buono RJ	2021	684	9,861	Genetic Variation in PADI6-PADI4 on 1p36.13 Is Associated with Common Forms of Human Generalized Epilepsy.
GCST90053847	Buono RJ	2021	684	9,861	Genetic Variation in PADI6-PADI4 on 1p36.13 Is Associated with Common Forms of Human Generalized Epilepsy.
GCST90043753	Jiang L	2021	290	456,058	A generalized linear mixed model association tool for biobank-scale data.
GCST90053846	Buono RJ	2021	143	4,627	Genetic Variation in PADI6-PADI4 on 1p36.13 Is Associated with Common Forms of Human Generalized Epilepsy.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	1
Tier 3: regulatory	0
Tier 4: intronic/intergenic	49

MAF distribution

Bucket	Variants
common (>=0.05)	48
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	2

Functional consequences

Consequence	Count
intron_variant	35
intergenic_variant	12
unknown	2
3_prime_UTR_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs11688767	2	57761059	A>G,T	0.05	intron_variant	EIF2S2P7 - ACTG1P22	7e-21	Tier 4: intronic/intergenic
rs2678901	2	57911516	A>C,G	0.05	intron_variant	VRK2	1e-18	Tier 4: intronic/intergenic
rs11191156	10	101943006	A>G	0.05	intron_variant	ARMH3	4e-14	Tier 4: intronic/intergenic
rs77876353	2	57823121	A>G	0.05	intron_variant	ACTG1P22 - VRK2	2e-12	Tier 4: intronic/intergenic
rs4596374	5	114885808	C>A,T	0.05	intergenic_variant	LINC01957 - TRIM36	3e-12	Tier 4: intronic/intergenic
rs2780103	9	83959653	C>G,T	0.05	intron_variant	HNRNPK-AS1	4e-12	Tier 4: intronic/intergenic
rs7277479	21	30789699	A>G,T	0.05	intergenic_variant	KRTAP21-1 - KRTAP8-2P	9e-12	Tier 4: intronic/intergenic
rs1402398	2	57815106	G>A	0.36	intron_variant	ACTG1P22 - VRK2	1e-11	Tier 4: intronic/intergenic
rs62151809	2	103816798	C>T	0.05	intron_variant	CAPZBP1 - LINC01965	1e-11	Tier 4: intronic/intergenic
rs12997934	2	57702660	C>A,G	0.05	intron_variant	EIF2S2P7 - ACTG1P22	4e-11	Tier 4: intronic/intergenic
rs1463849	4	31147224	A>G,T	0.05	intergenic_variant	PCDH7 - LINC02497	4e-11	Tier 4: intronic/intergenic
rs9861238	3	36284531	A>G	0.05	intron_variant	RFC3P1 - STAC	1e-10	Tier 4: intronic/intergenic
rs6545674	2	57946486	A>G	0.05	intron_variant	VRK2	2e-10	Tier 4: intronic/intergenic
rs2905552	5	137293595	G>A,C	0.05	intron_variant	SPOCK1	2e-10	Tier 4: intronic/intergenic
rs2585398	17	8151542	C>A	0.05	intron_variant	PER1	2e-10	Tier 4: intronic/intergenic
rs469999	22	48241244	A>G	0.05	intergenic_variant	EPIC1 - MIR3201	3e-10	Tier 4: intronic/intergenic
rs75483641	19	2123929	C>G,T	0.05	intron_variant	AP3D1	5e-10	Tier 4: intronic/intergenic
rs739431	3	50217873	A>G	0.05	intron_variant	SLC38A3	5e-10	Tier 4: intronic/intergenic
rs13416557	2	58453545	G>C,T	0.05	intron_variant	LINC01122	7e-10	Tier 4: intronic/intergenic
rs6721964	2	190713628	G>A,C	0.05	intron_variant	NAB1 - GLS	7e-10	Tier 4: intronic/intergenic
rs2236951	3	50383650	T>C	0.05	intron_variant	CACNA2D2	1e-09	Tier 4: intronic/intergenic
rs1044352	4	31146252	G>A,C,T	0.42	3_prime_UTR_variant	PCDH7	2e-09	Tier 2: splice/UTR
rs68082256	6	16971344	G>A	0.2	intergenic_variant	ATXN1-AS1 - STMND1	2e-09	Tier 4: intronic/intergenic
rs4807201	19	2120315	T>C	0.05	intron_variant	AP3D1	2e-09	Tier 4: intronic/intergenic
rs16955463	17	48322135	G>T	0.05	intron_variant	SKAP1	2e-09	Tier 4: intronic/intergenic
rs876793	1	237688783	T>A,C,G	0.05	intron_variant	RYR2	3e-09	Tier 4: intronic/intergenic
rs7211143	17	48470019	A>G,T	0.05	intergenic_variant	SKAP1 - Y_RNA	3e-09	Tier 4: intronic/intergenic
rs62014006	16	7294940	T>A,C,G	0.05	intron_variant	RBFOX1	4e-09	Tier 4: intronic/intergenic
rs264980	2	103653521	C>A,T	0.05	intergenic_variant	CAPZBP1 - LINC01965	5e-09	Tier 4: intronic/intergenic
rs114131287	12	51938539	T>A	0.05	intergenic_variant	ACVRL1 - ACVR1B	5e-09	Tier 4: intronic/intergenic

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

344 likely benign, 170 uncertain significance, 51 conflicting classifications of pathogenicity, 25 benign, 7 benign/likely benign, 2 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069674	NC_000005.9:g.(?161128494)(161580374_?)del	GABRA1	Pathogenic	criteria provided, single submitter
1164001	NM_001348946.2(ABCB1):c.2678C>A (p.Ser893Tyr)	ABCB1	Likely pathogenic	no assertion criteria provided
1066045	NM_001127644.2(GABRA1):c.124T>C (p.Phe42Leu)	GABRA1	Likely pathogenic	criteria provided, single submitter
1000691	NM_021098.3(CACNA1H):c.4814C>A (p.Pro1605His)	CACNA1H	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1001887	NM_021098.3(CACNA1H):c.2231G>A (p.Arg744Gln)	CACNA1H	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1004965	NM_021098.3(CACNA1H):c.3758G>A (p.Arg1253His)	CACNA1H	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1005249	NM_021098.3(CACNA1H):c.1673C>T (p.Ser558Leu)	CACNA1H	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1008653	NM_021098.3(CACNA1H):c.3884T>C (p.Met1295Thr)	CACNA1H	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1011552	NM_021098.3(CACNA1H):c.391G>A (p.Glu131Lys)	CACNA1H	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1011782	NM_021098.3(CACNA1H):c.4823G>A (p.Arg1608His)	CACNA1H	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1013845	NM_021098.3(CACNA1H):c.560C>T (p.Ser187Leu)	CACNA1H	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1015188	NM_021098.3(CACNA1H):c.3584G>A (p.Arg1195Gln)	CACNA1H	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1015270	NM_021098.3(CACNA1H):c.6398G>T (p.Arg2133Leu)	CACNA1H	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1015641	NM_021098.3(CACNA1H):c.1691G>A (p.Arg564His)	CACNA1H	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1016006	NM_021098.3(CACNA1H):c.3347G>A (p.Gly1116Glu)	CACNA1H	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1020407	NM_021098.3(CACNA1H):c.3143T>C (p.Leu1048Pro)	CACNA1H	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1021653	NM_021098.3(CACNA1H):c.2995A>G (p.Met999Val)	CACNA1H	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1023131	NM_021098.3(CACNA1H):c.3614G>C (p.Arg1205Pro)	CACNA1H	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1023368	NM_021098.3(CACNA1H):c.6563G>A (p.Ser2188Asn)	CACNA1H	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1025264	NM_021098.3(CACNA1H):c.3467G>A (p.Arg1156His)	CACNA1H	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1032113	NM_021098.3(CACNA1H):c.2789+16C>T	CACNA1H	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1032116	NM_021098.3(CACNA1H):c.974C>T (p.Pro325Leu)	CACNA1H	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1038757	NM_021098.3(CACNA1H):c.1046C>T (p.Ser349Leu)	CACNA1H	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1041003	NM_021098.3(CACNA1H):c.6281C>T (p.Ser2094Leu)	CACNA1H	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1042192	NM_021098.3(CACNA1H):c.2209G>A (p.Gly737Ser)	CACNA1H	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1044087	NM_021098.3(CACNA1H):c.2545C>T (p.Pro849Ser)	CACNA1H	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1044825	NM_021098.3(CACNA1H):c.1835A>C (p.Asn612Thr)	CACNA1H	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1046542	NM_021098.3(CACNA1H):c.4741C>G (p.Leu1581Val)	CACNA1H	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1051387	NM_021098.3(CACNA1H):c.1000C>T (p.Arg334Cys)	CACNA1H	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1051672	NM_021098.3(CACNA1H):c.919G>A (p.Gly307Ser)	CACNA1H	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 56 · 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
STAT4	STAT4	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
SHROOM4	Strong	X-linked	idiopathic generalized epilepsy	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SHROOM4	Orphanet:85288	X-linked intellectual disability, Stocco Dos Santos type
ATXN1	Orphanet:98755	Spinocerebellar ataxia type 1
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
STAT4	Orphanet:117	Behçet disease
STAT4	Orphanet:536	Systemic lupus erythematosus
STAT4	Orphanet:85408	Rheumatoid factor-negative polyarticular juvenile idiopathic arthritis
STAT4	Orphanet:85410	Oligoarticular juvenile idiopathic arthritis
STAT4	Orphanet:93552	Pediatric systemic lupus erythematosus
BCL11A	Orphanet:251380	Hereditary persistence of fetal hemoglobin-sickle cell disease syndrome
BCL11A	Orphanet:619233	Hereditary persistence of fetal hemoglobin-intellectual disability syndrome
CACNA1H	Orphanet:642671	Familial hyperaldosteronism type IV
CACNA1H	Orphanet:64280	Childhood absence epilepsy
CACNB4	Orphanet:211067	Episodic ataxia type 5
CACNB4	Orphanet:307	Juvenile myoclonic epilepsy
CASR	Orphanet:417	Neonatal severe primary hyperparathyroidism
CASR	Orphanet:428	Autosomal dominant hypocalcemia
CASR	Orphanet:676	Autosomal dominant hereditary chronic pancreatitis
CASR	Orphanet:93372	Familial hypocalciuric hypercalcemia type 1
ADGRV1	Orphanet:231178	Usher syndrome type 2
ADGRV1	Orphanet:36387	Genetic epilepsy with febrile seizure plus
FANCL	Orphanet:84	Fanconi anemia
TTC21B	Orphanet:474	Jeune syndrome
TTC21B	Orphanet:93591	Infantile nephronophthisis
PNPO	Orphanet:79096	Pyridoxamine-5-phosphate deficiency-developmental and epileptic encephalopathy
ABCA3	Orphanet:2032	Idiopathic pulmonary fibrosis
ABCA3	Orphanet:217563	Neonatal acute respiratory distress syndrome
ABCA3	Orphanet:440402	Interstitial lung disease due to ABCA3 deficiency
ABCA3	Orphanet:685082	Pediatric acute respiratory distress syndrome
GABRA1	Orphanet:307	Juvenile myoclonic epilepsy
GABRA1	Orphanet:33069	Dravet syndrome
GABRA1	Orphanet:64280	Childhood absence epilepsy
GABRA2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
GABRD	Orphanet:1606	1p36 deletion syndrome
GABRD	Orphanet:307	Juvenile myoclonic epilepsy

Cohort genes → proteins

37 cohort genes, 37 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	15
multi_evidence	22

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SHROOM4	HGNC:29215	ENSG00000158352	Q9ULL8	Protein Shroom4	gencc
ATXN1	HGNC:10548	ENSG00000124788	P54253	Ataxin-1	gwas
SCN1A	HGNC:10585	ENSG00000144285	P35498	Sodium channel protein type 1 subunit alpha	gwas
SCN2A	HGNC:10588	ENSG00000136531	Q99250	Sodium channel protein type 2 subunit alpha	gwas
SCN3A	HGNC:10590	ENSG00000153253	Q9NY46	Sodium channel protein type 3 subunit alpha	gwas
STAT4	HGNC:11365	ENSG00000138378	Q14765	Signal transducer and activator of transcription 4	gwas
TIMP2	HGNC:11821	ENSG00000035862	P16035	Metalloproteinase inhibitor 2	clinvar
USP25	HGNC:12624	ENSG00000155313	Q9UHP3	Ubiquitin carboxyl-terminal hydrolase 25	clinvar
VRK2	HGNC:12719	ENSG00000028116	Q86Y07	Serine/threonine-protein kinase VRK2	gwas
BCL11A	HGNC:13221	ENSG00000119866	Q9H165	BCL11 transcription factor A	gwas
CACNA1H	HGNC:1395	ENSG00000196557	O95180	Voltage-dependent T-type calcium channel subunit alpha-1H	clinvar
CACNB4	HGNC:1404	ENSG00000182389	O00305	Voltage-dependent L-type calcium channel subunit beta-4	clinvar
ANTKMT	HGNC:14152	ENSG00000103254	Q9BQD7	Adenine nucleotide translocase lysine N-methyltransferase	clinvar
CASR	HGNC:1514	ENSG00000036828	P41180	Extracellular calcium-sensing receptor	clinvar
KCNIP1	HGNC:15521	ENSG00000182132	Q9NZI2	A-type potassium channel modulatory protein KCNIP1	clinvar
RAB11FIP3	HGNC:17224	ENSG00000090565	O75154	Rab11 family-interacting protein 3	clinvar
ADGRV1	HGNC:17416	ENSG00000164199	Q8WXG9	Adhesion G-protein coupled receptor V1	clinvar
RBFOX1	HGNC:18222	ENSG00000078328	Q9NWB1	RNA binding protein fox-1 homolog 1	clinvar
CHTF18	HGNC:18435	ENSG00000127586	Q8WVB6	Chromosome transmission fidelity protein 18 homolog	clinvar
FANCL	HGNC:20748	ENSG00000115392	Q9NW38	E3 ubiquitin-protein ligase FANCL	gwas
CALML6	HGNC:24193	ENSG00000169885	Q8TD86	Calmodulin-like protein 6	clinvar
TTC21B	HGNC:25660	ENSG00000123607	Q7Z4L5	Tetratricopeptide repeat protein 21B	gwas
RBFOX3	HGNC:27097	ENSG00000167281	A6NFN3	RNA binding protein fox-1 homolog 3	clinvar
PNPO	HGNC:30260	ENSG00000108439	Q9NVS9	Pyridoxine-5’-phosphate oxidase	gwas
C1QTNF8	HGNC:31374	ENSG00000184471	P60827	Complement C1q tumor necrosis factor-related protein 8	clinvar
ABCA3	HGNC:33	ENSG00000167972	Q99758	Phospholipid-transporting ATPase ABCA3	clinvar
ABCB1	HGNC:40	ENSG00000085563	P08183	ATP-dependent translocase ABCB1	clinvar
GABRA1	HGNC:4075	ENSG00000022355	P14867	Gamma-aminobutyric acid receptor subunit alpha-1	clinvar
GABRA2	HGNC:4076	ENSG00000151834	P47869	Gamma-aminobutyric acid receptor subunit alpha-2	gwas
GABRD	HGNC:4084	ENSG00000187730	O14764	Gamma-aminobutyric acid receptor subunit delta	clinvar
GABRG2	HGNC:4087	ENSG00000113327	P18507	Gamma-aminobutyric acid receptor subunit gamma-2	clinvar
ANKRD65	HGNC:42950	ENSG00000235098	E5RJM6	Ankyrin repeat domain-containing protein 65	clinvar
GRIK1	HGNC:4579	ENSG00000171189	P39086	Glutamate receptor ionotropic, kainate 1	gwas
KCNN2	HGNC:6291	ENSG00000080709	Q9H2S1	Small conductance calcium-activated potassium channel protein 2	gwas
ARL5A	HGNC:696	ENSG00000162980	Q9Y689	ADP-ribosylation factor-like protein 5A	clinvar
MMP8	HGNC:7175	ENSG00000118113	P22894	Neutrophil collagenase	gwas
PCDH7	HGNC:8659	ENSG00000169851	O60245	Protocadherin-7	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SHROOM4	Protein Shroom4	Probable regulator of cytoskeletal architecture that plays an important role in development.
ATXN1	Ataxin-1	Chromatin-binding factor that repress Notch signaling in the absence of Notch intracellular domain by acting as a CBF1 corepressor.
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.
STAT4	Signal transducer and activator of transcription 4	Transcriptional regulator mainly expressed in hematopoietic cells that plays a critical role in cellular growth, differentiation and immune response.
TIMP2	Metalloproteinase inhibitor 2	Complexes with metalloproteinases (such as collagenases) and irreversibly inactivates them by binding to their catalytic zinc cofactor.
USP25	Ubiquitin carboxyl-terminal hydrolase 25	Deubiquitinating enzyme that hydrolyzes ubiquitin moieties conjugated to substrates and thus, functions in various biological processes including inflammation and immune response.
VRK2	Serine/threonine-protein kinase VRK2	Serine/threonine kinase that regulates several signal transduction pathways.
BCL11A	BCL11 transcription factor A	Transcription factor.
CACNA1H	Voltage-dependent T-type calcium channel subunit alpha-1H	Voltage-sensitive calcium channel that gives rise to T-type calcium currents.
CACNB4	Voltage-dependent L-type calcium channel subunit beta-4	The beta subunit of voltage-dependent calcium channels contributes to the function of the calcium channel by increasing peak calcium current, shifting the voltage dependencies of activation and inactivation, modulating G protein inhibition…
ANTKMT	Adenine nucleotide translocase lysine N-methyltransferase	Mitochondrial protein-lysine N-methyltransferase that trimethylates adenine nucleotide translocases ANT2/SLC25A5 and ANT3/SLC25A6, thereby regulating mitochondrial respiration.
CASR	Extracellular calcium-sensing receptor	G-protein-coupled receptor that senses changes in the extracellular concentration of calcium ions and plays a key role in maintaining calcium homeostasis.
KCNIP1	A-type potassium channel modulatory protein KCNIP1	Regulatory subunit of Kv4/D (Shal)-type voltage-gated rapidly inactivating A-type potassium channels.
RAB11FIP3	Rab11 family-interacting protein 3	Downstream effector molecule for Rab11 GTPase which is involved in endocytic trafficking, cytokinesis and intracellular ciliogenesis by participating in membrane delivery.
ADGRV1	Adhesion G-protein coupled receptor V1	G-protein coupled receptor which has an essential role in the development of hearing and vision.
RBFOX1	RNA binding protein fox-1 homolog 1	RNA-binding protein that regulates alternative splicing events by binding to 5’-UGCAUGU-3’ elements.
CHTF18	Chromosome transmission fidelity protein 18 homolog	Chromosome cohesion factor involved in sister chromatid cohesion and fidelity of chromosome transmission.
FANCL	E3 ubiquitin-protein ligase FANCL	Ubiquitin ligase protein that mediates monoubiquitination of FANCD2 in the presence of UBE2T, a key step in the DNA damage pathway.
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).
RBFOX3	RNA binding protein fox-1 homolog 3	Pre-mRNA alternative splicing regulator.
PNPO	Pyridoxine-5’-phosphate oxidase	Catalyzes the oxidation of either pyridoxine 5’-phosphate (PNP) or pyridoxamine 5’-phosphate (PMP) into pyridoxal 5’-phosphate (PLP).
C1QTNF8	Complement C1q tumor necrosis factor-related protein 8	May play a role as ligand of RXFP1.
ABCA3	Phospholipid-transporting ATPase ABCA3	Catalyzes the ATP-dependent transport of phospholipids such as phosphatidylcholine and phosphoglycerol from the cytoplasm into the lumen side of lamellar bodies, in turn participates in the lamellar bodies biogenesis and homeostasis of pul…
ABCB1	ATP-dependent translocase ABCB1	Translocates drugs and phospholipids across the membrane.
GABRA1	Gamma-aminobutyric acid receptor subunit alpha-1	Alpha subunit of the heteropentameric ligand-gated chloride channel gated by Gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain.
GABRA2	Gamma-aminobutyric acid receptor subunit alpha-2	Alpha subunit of the heteropentameric ligand-gated chloride channel gated by gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain.
GABRD	Gamma-aminobutyric acid receptor subunit delta	Delta subunit of the heteropentameric ligand-gated chloride channel gated by gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain.
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.
GRIK1	Glutamate receptor ionotropic, kainate 1	Ionotropic glutamate receptor that functions as a cation-permeable ligand-gated ion channel, gated by L-glutamate and the glutamatergic agonist kainic acid.
KCNN2	Small conductance calcium-activated potassium channel protein 2	Small conductance calcium-activated potassium channel that mediates the voltage-independent transmembrane transfer of potassium across the cell membrane through a constitutive interaction with calmodulin which binds the intracellular calci…
ARL5A	ADP-ribosylation factor-like protein 5A	Lacks ADP-ribosylation enhancing activity.
MMP8	Neutrophil collagenase	Can degrade fibrillar type I, II, and III collagens.

Protein-family classification

Druggable: 14 · Difficult: 6 · Unknown: 17 · Druggable fraction: 0.38

Family distribution

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

Family	Genes	Fold	FDR
Ion channel	5	15.1×	2e-04
Transporter	2	4.2×	0.368
Protease	2	2.0×	0.804
Scaffold/PPI	3	1.4×	0.815
GPCR	2	1.3×	0.830
Other/Unknown	17	0.8×	0.915
Kinase	1	0.8×	0.915
Transcription factor	3	0.7×	0.915
Enzyme (other)	2	0.7×	0.915

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SHROOM4	Scaffold/PPI	no		PDZ, ASD2_dom, Shroom_fam
ATXN1	Other/Unknown	no		Ataxin_AXH_dom, Ataxin-1_N, Ataxin_AXH_dom_sf
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
STAT4	Transcription factor	no		SH2, STAT, p53-like_TF_DNA-bd_sf
TIMP2	Enzyme (other)	yes	3.4.24.22	Netrin_domain, TIMP, TIMP-like_OB-fold
USP25	Protease	yes		Peptidase_C19_UCH, UIM_dom, UBA-like_sf
VRK2	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
BCL11A	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Dev/Hematopoietic_TF
CACNA1H	Ion channel	yes		VDCC_T_a1, Ion_trans_dom, Volt_channel_dom_sf
CACNB4	Scaffold/PPI	no		VDCC_L_bsu, SH3_domain, GK/Ca_channel_bsu
ANTKMT	Other/Unknown	no		FAM173A/B, SAM-dependent_MTases_sf
CASR	GPCR	yes		GPCR_3_Ca_sens_rcpt-rel, GPCR_3, ANF_lig-bd_rcpt
KCNIP1	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
RAB11FIP3	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, Rab-bd_FIP-RBD
ADGRV1	GPCR	yes		GPCR_2_secretin-like, Calx_beta, EPTP
RBFOX1	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, RBFOX1-3
CHTF18	Other/Unknown	no		AAA+_ATPase, ATPase_AAA_core, P-loop_NTPase
FANCL	Transcription factor	no	2.3.2.27	Znf_RING/FYVE/PHD, UBQ-conjugating_enzyme/RWD, FancL_WD-rpt_cont_dom
CALML6	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
TTC21B	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, TTC21A/TTC21B
RBFOX3	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, RBFOX1-3
PNPO	Enzyme (other)	yes	1.4.3.5	Pyridox_Oxase, Pyridox_Oxase_N, Split_barrel_FMN-bd
C1QTNF8	Other/Unknown	no		C1q_dom, Collagen, Tumour_necrosis_fac-like_dom
ABCA3	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC2_TM
ABCB1	Transporter	yes	7.6.2.2	ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC1_TM_dom
GABRA1	Other/Unknown	no		GABAAa_rcpt, GABBAa1_rcpt, GABAA/Glycine_rcpt
GABRA2	Other/Unknown	no		GABAAa_rcpt, GABBAa2_rcpt, GABAA/Glycine_rcpt
GABRD	Other/Unknown	no		GABAA/Glycine_rcpt, Neurotrans-gated_channel_TM, Neur_channel
GABRG2	Other/Unknown	no		GABRG-1/4, GABBAg2_rcpt, GABAA/Glycine_rcpt
ANKRD65	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf, Dendritic_Spine_Reg/Scaffold
GRIK1	Other/Unknown	no		Iontro_rcpt_C, Iono_Glu_rcpt_met, ANF_lig-bd_rcpt
KCNN2	Ion channel	yes		CaM-bd_dom, K_chnl_dom, K_chnl_Ca-activ_SK
ARL5A	Other/Unknown	no		Small_GTP-bd, Small_GTPase_ARF/SAR, Small_GTPase_ARF
MMP8	Protease	yes	3.4.24.34	Hemopexin-like_dom, Pept_M10_metallopeptidase, Peptidoglycan-bd-like
PCDH7	Other/Unknown	no		Cadherin-like_dom, Cadherin_N, Protocadherin

Expression context

Cohort genes with no expression data: 0.

34 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)	37
unknown	0

Top tissues across cohort

Tissue	Cohort genes
middle temporal gyrus	7
Brodmann (1909) area 23	6
endothelial cell	4
calcaneal tendon	4
skeletal muscle tissue of rectus abdominis	3
lateral nuclear group of thalamus	3
primary visual cortex	3
cortical plate	3
anterior cingulate cortex	3
cingulate cortex	3
right hemisphere of cerebellum	3
right adrenal gland	3
cerebellar hemisphere	3
right uterine tube	3
tendon of biceps brachii	2
cerebellar vermis	2
sperm	2
mucosa of transverse colon	2
kidney epithelium	2
right adrenal gland cortex	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SHROOM4	190	broad	marker	buccal mucosa cell, tendon of biceps brachii, left ventricle myocardium
ATXN1	295	ubiquitous	marker	endothelial cell, Brodmann (1909) area 23, skeletal muscle tissue of rectus abdominis
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
STAT4	201	broad	marker	granulocyte, sperm, middle temporal gyrus
TIMP2	292	ubiquitous	marker	tendon of biceps brachii, synovial joint, stromal cell of endometrium
USP25	285	ubiquitous	marker	sperm, male germ cell, skeletal muscle tissue of rectus abdominis
VRK2	280	ubiquitous	marker	monocyte, mononuclear cell, calcaneal tendon
BCL11A	247	ubiquitous	marker	cortical plate, ganglionic eminence, primary visual cortex
CACNA1H	166	broad	marker	lower esophagus muscularis layer, muscle layer of sigmoid colon, lower esophagus
CACNB4	201	broad	marker	cerebellar vermis, lateral nuclear group of thalamus, primary visual cortex
ANTKMT	243	ubiquitous	marker	anterior cingulate cortex, cingulate cortex, mucosa of transverse colon
CASR	63	tissue_specific	marker	islet of Langerhans, diaphragm, hair follicle
KCNIP1	162	broad	marker	nucleus accumbens, anterior cingulate cortex, cingulate cortex
RAB11FIP3	246	ubiquitous	marker	kidney epithelium, pancreatic ductal cell, right hemisphere of cerebellum
ADGRV1	196	broad	marker	right adrenal gland cortex, right adrenal gland, left adrenal gland
RBFOX1	220	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, cortical plate
CHTF18	188	ubiquitous	yes	right testis, left testis, mucosa of transverse colon
FANCL	293	ubiquitous	marker	pituitary gland, adenohypophysis, calcaneal tendon
CALML6	163	tissue_specific	yes	hindlimb stylopod muscle, skeletal muscle tissue of rectus abdominis, skeletal muscle tissue of biceps brachii
TTC21B	179	ubiquitous	marker	right uterine tube, calcaneal tendon, cerebellar hemisphere
RBFOX3	177	broad	marker	right hemisphere of cerebellum, cerebellar cortex, cerebellar hemisphere
PNPO	230	ubiquitous	marker	right lobe of liver, liver, kidney epithelium
C1QTNF8	51		yes	right uterine tube, ascending aorta, thoracic aorta
ABCA3	222	ubiquitous	marker	lower lobe of lung, upper lobe of lung, upper lobe of left lung
ABCB1	232	broad	marker	right adrenal gland, right adrenal gland cortex, left adrenal gland cortex
GABRA1	130	tissue_specific	marker	lateral nuclear group of thalamus, endothelial cell, middle temporal gyrus
GABRA2	195	broad	marker	frontal pole, entorhinal cortex, postcentral gyrus
GABRD	176	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 22.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CALML6	6,595
ATXN1	4,465
RBFOX3	4,442
ABCB1	4,426
RBFOX1	2,990
SCN2A	2,810
TIMP2	2,806
CASR	2,692
KCNIP1	2,676
GABRA1	2,469

Intra-cohort edges

A	B	Sources
ANTKMT	FANCL	biogrid_interaction, intact
ATXN1	RBFOX1	intact, string_interaction
CACNA1H	GABRA1	string_interaction
CACNA1H	GABRD	string_interaction
CACNA1H	GABRG2	string_interaction
CACNB4	GABRA1	string_interaction
CACNB4	GABRD	string_interaction
CALML6	KCNN2	string_interaction
FANCL	VRK2	string_interaction
GABRA1	GABRG2	biogrid_interaction, intact
GABRA1	GRIK1	string_interaction
GABRA1	SCN1A	string_interaction
GABRA1	SCN2A	string_interaction
GABRA2	GABRG2	biogrid_interaction
GABRD	SCN1A	string_interaction
GABRG2	SCN1A	string_interaction
GABRG2	SCN2A	string_interaction
MMP8	TIMP2	string_interaction
PNPO	SCN1A	string_interaction
RBFOX1	RBFOX3	biogrid_interaction
SCN1A	SCN2A	biogrid_interaction, string_interaction
SCN2A	SCN3A	intact

Structural data

PDB: 30 · AlphaFold-only: 7 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GABRA1	P14867	86
GABRG2	P18507	75
CASR	P41180	31
MMP8	P22894	25
ABCB1	P08183	24
BCL11A	Q9H165	17
KCNN2	Q9H2S1	16
GRIK1	P39086	11
KCNIP1	Q9NZI2	10
CHTF18	Q8WVB6	10
FANCL	Q9NW38	8
GABRA2	P47869	8
ATXN1	P54253	7
USP25	Q9UHP3	7
GABRD	O14764	7
PNPO	Q9NVS9	6
SCN2A	Q99250	5
VRK2	Q86Y07	5
CACNA1H	O95180	5
RAB11FIP3	O75154	5
TIMP2	P16035	4
RBFOX1	Q9NWB1	4
ARL5A	Q9Y689	4
TTC21B	Q7Z4L5	3
SCN3A	Q9NY46	2
ABCA3	Q99758	2
SHROOM4	Q9ULL8	1
SCN1A	P35498	1
CACNB4	O00305	1
PCDH7	O60245	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
STAT4	Q14765	86.87
ANKRD65	E5RJM6	85.07
ANTKMT	Q9BQD7	82.01
C1QTNF8	P60827	78.89
CALML6	Q8TD86	78.48
RBFOX3	A6NFN3	62.27
ADGRV1	Q8WXG9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 100. Enrichment computed across 37 evidence-associated genes (29 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 29 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interaction between L1 and Ankyrins	3	38.1×	0.002	SCN1A, SCN2A, SCN3A
Phase 0 - rapid depolarisation	3	35.8×	0.002	SCN1A, SCN2A, SCN3A
Muscle contraction	5	13.3×	0.002	SCN1A, SCN2A, SCN3A, CACNA1H, KCNIP1
Nervous system development	6	8.9×	0.002	SCN1A, SCN2A, SCN3A, CACNA1H, CACNB4, ADGRV1
GABA receptor activation	3	32.8×	0.002	GABRA1, GABRA2, GABRG2
Cardiac conduction	4	15.0×	0.002	SCN1A, SCN2A, SCN3A, KCNIP1
Axon guidance	5	7.8×	0.006	SCN1A, SCN2A, SCN3A, CACNA1H, CACNB4
L1CAM interactions	3	12.4×	0.022	SCN1A, SCN2A, SCN3A
Defective ABCA3 causes SMDP3	1	393.8×	0.025	ABCA3
Sensory perception of taste	2	23.2×	0.028	SCN2A, SCN3A
Sensory Perception	3	9.8×	0.028	SCN2A, SCN3A, KCNN2
Activation of Na-permeable kainate receptors	1	196.9×	0.030	GRIK1
Activation of Matrix Metalloproteinases	2	21.3×	0.030	TIMP2, MMP8
Sensory perception of sweet, bitter, and umami (glutamate) taste	2	19.2×	0.030	SCN2A, SCN3A
Signaling by ERBB4	2	18.8×	0.030	GABRA1, GABRG2
NCAM signaling for neurite out-growth	2	18.8×	0.030	CACNA1H, CACNB4
NCAM1 interactions	2	17.1×	0.033	CACNA1H, CACNB4
Vitamin B6 activation to pyridoxal phosphate	1	131.3×	0.040	PNPO
Diseases associated with surfactant metabolism	1	98.5×	0.051	ABCA3
Abacavir transmembrane transport	1	78.8×	0.054	ABCB1
MECP2 regulates transcription factors	1	78.8×	0.054	RBFOX1
Acetylcholine inhibits contraction of outer hair cells	1	78.8×	0.054	KCNN2
Developmental Biology	6	3.0×	0.054	SCN1A, SCN2A, SCN3A, CACNA1H, CACNB4, ADGRV1
Phase 1 - inactivation of fast Na+ channels	1	56.3×	0.071	KCNIP1
Abacavir ADME	1	49.2×	0.075	ABCB1
Atorvastatin ADME	1	49.2×	0.075	ABCB1
Interleukin-23 signaling	1	43.8×	0.076	STAT4
Prednisone ADME	1	43.8×	0.076	ABCB1
Ca2+ activated K+ channels	1	39.4×	0.076	KCNN2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 36 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
gamma-aminobutyric acid signaling pathway	5	75.5×	2e-06	CACNB4, GABRA1, GABRA2, GABRD, GABRG2
chloride transmembrane transport	5	33.0×	6e-05	CASR, GABRA1, GABRA2, GABRD, GABRG2
synaptic transmission, GABAergic	4	55.1×	8e-05	GABRA1, GABRA2, GABRD, GABRG2
cardiac muscle cell action potential involved in contraction	3	58.5×	0.001	SCN1A, SCN2A, SCN3A
inhibitory synapse assembly	3	52.0×	0.002	GABRA1, GABRA2, GABRG2
membrane depolarization during action potential	2	93.6×	0.009	SCN1A, SCN3A
cellular response to L-glutamate	2	93.6×	0.009	BCL11A, ABCB1
neuronal action potential propagation	2	78.0×	0.011	SCN1A, CACNB4
sodium ion transport	3	22.6×	0.011	SCN1A, SCN2A, SCN3A
sodium ion transmembrane transport	3	16.9×	0.022	SCN1A, SCN2A, SCN3A
positive regulation of protein homooligomerization	1	468.1×	0.028	ABCA3
pyridoxal 5’-phosphate biosynthetic process	1	468.1×	0.028	PNPO
daunorubicin transport	1	468.1×	0.028	ABCB1
terpenoid transport	1	468.1×	0.028	ABCB1
cellular response to nonylphenol	1	468.1×	0.028	ABCB1
positive regulation of establishment of Sertoli cell barrier	1	468.1×	0.028	ABCB1
negative regulation of neuron remodeling	1	468.1×	0.028	BCL11A
cellular response to borneol	1	468.1×	0.028	ABCB1
response to codeine	1	468.1×	0.028	ABCB1
negative regulation of branching morphogenesis of a nerve	1	468.1×	0.028	BCL11A
positive regulation of response to drug	1	468.1×	0.028	ABCB1
regulation of potassium ion transmembrane transport	2	34.7×	0.028	KCNIP1, KCNN2
nervous system development	5	6.4×	0.028	SCN2A, ADGRV1, RBFOX1, RBFOX3, GRIK1
adult walking behavior	2	27.5×	0.029	SCN1A, CACNB4
regulation of heart contraction	2	27.5×	0.029	CACNA1H, KCNIP1
pyridoxine biosynthetic process	1	234.1×	0.030	PNPO
intrinsic apoptotic signaling pathway in response to osmotic stress	1	234.1×	0.030	SCN2A
hormone transport	1	234.1×	0.030	ABCB1
cellular response to mycotoxin	1	234.1×	0.030	ABCB1
pyridoxamine metabolic process	1	234.1×	0.030	PNPO

Therapeutics

Drug target analysis

Approved (phase 4): 13 · Phase ≥3: 14 · Phased (≥1): 15 · Undrugged: 22

Druggability breadth: 20 of 37 evidence-associated genes (54%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

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

Symbol	Example approved molecule
SCN1A	MEXILETINE HYDROCHLORIDE
SCN2A	BEPRIDIL
SCN3A	BEPRIDIL
VRK2	RUXOLITINIB
CACNA1H	PIMOZIDE
CACNB4	NIMODIPINE
CASR	CINACALCET HYDROCHLORIDE
ABCB1	PROGESTERONE
GABRA1	DIAZEPAM
GABRA2	ENZALUTAMIDE
GABRD	ENZALUTAMIDE
GABRG2	ENZALUTAMIDE
MMP8	DOXYCYCLINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ABCB1	119	4
SCN2A	99	4
SCN1A	94	4
SCN3A	93	4
GABRA1	60	4
GABRG2	55	4
GABRA2	46	4
GABRD	16	4
CACNA1H	10	4
CASR	10	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MEXILETINE HYDROCHLORIDE	4	SCN1A
BEPRIDIL	4	SCN1A, SCN2A, SCN3A
DIBUCAINE	4	SCN1A, SCN2A, SCN3A
ARTICAINE	4	SCN1A, SCN2A, SCN3A
BUPIVACAINE	4	SCN1A, SCN2A, SCN3A
IMIPRAMINE	4	SCN1A, SCN2A, SCN3A
DROPERIDOL	4	SCN1A, SCN2A, SCN3A
DICYCLOMINE	4	SCN1A, SCN2A, SCN3A
TETRABENAZINE	4	SCN1A, SCN2A, SCN3A
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
QUINIDINE	4	ABCB1, SCN1A, SCN2A, SCN3A
FELODIPINE	4	ABCB1, SCN1A, SCN2A, SCN3A
PHENYTOIN	4	SCN1A, SCN2A, SCN3A
QUININE	4	ABCB1, SCN1A, SCN2A, SCN3A
NISOLDIPINE	4	ABCB1, SCN1A, SCN2A, SCN3A
NIFEDIPINE	4	SCN1A, SCN2A, SCN3A
PRAZOSIN	4	SCN1A, SCN2A, SCN3A
DILTIAZEM	4	ABCB1, SCN1A, SCN2A, SCN3A
PRENYLAMINE	4	SCN1A, SCN2A, SCN3A
COCAINE	4	SCN1A, SCN2A, SCN3A
TRIFLUOPERAZINE	4	ABCB1, SCN1A, SCN2A, SCN3A
CINNARIZINE	4	SCN1A, SCN2A, SCN3A
THIORIDAZINE	4	SCN1A, SCN2A, SCN3A
ETIDOCAINE	4	SCN1A, SCN2A, SCN3A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 5.

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

Symbol	Assays	Type breakdown
ABCB1	3,063	Binding:2135, Functional:746, ADMET:182
GABRG2	1,155	Binding:940, Functional:201, ADMET:10, Toxicity:4
GABRA1	842	Binding:701, Functional:124, ADMET:13, Toxicity:4
GABRA2	385	Binding:327, Functional:52, ADMET:3, Toxicity:3
MMP8	238	Binding:225, ADMET:9, Functional:3, Unclassified:1
SCN2A	203	Binding:172, Functional:20, ADMET:10, Toxicity:1
GABRD	203	Binding:184, Functional:15, Toxicity:3, ADMET:1
SCN1A	149	Binding:115, Functional:18, ADMET:14, Toxicity:2
VRK2	146	Binding:146
CACNA1H	124	Binding:102, Functional:17, ADMET:4, Toxicity:1
SCN3A	102	Binding:79, Functional:18, ADMET:4, Toxicity:1
GRIK1	70	Binding:55, Functional:15
CASR	45	Functional:32, Binding:13
KCNN2	22	Binding:22
STAT4	20	Binding:20
USP25	19	Binding:19
CACNB4	13	Binding:13
PNPO	2	Binding:2
CHTF18	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TIMP2	3.4.24.22	stromelysin 2
FANCL	2.3.2.27	RING-type E3 ubiquitin transferase
PNPO	1.4.3.5	pyridoxal 5’-phosphate synthase
ABCB1	7.6.2.2, 7.6.2.3	ABC-type xenobiotic transporter, ABC-type glutathione-S-conjugate transporter
MMP8	3.4.24.34	neutrophil collagenase

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
VRK2	146
CACNA1H	124
ABCB1	3,063
GABRA1	842
GABRA2	385
GABRD	203
GABRG2	1,155
MMP8	238

Pharmacogenomics

Cohort genes with a PharmGKB record: 37; 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)
MEXILETINE HYDROCHLORIDE	4	SCN1A
BEPRIDIL	4	SCN1A, SCN2A, SCN3A
DIBUCAINE	4	SCN1A, SCN2A, SCN3A
ARTICAINE	4	SCN1A, SCN2A, SCN3A
BUPIVACAINE	4	SCN1A, SCN2A, SCN3A
IMIPRAMINE	4	SCN1A, SCN2A, SCN3A
DROPERIDOL	4	SCN1A, SCN2A, SCN3A
DICYCLOMINE	4	SCN1A, SCN2A, SCN3A
TETRABENAZINE	4	SCN1A, SCN2A, SCN3A
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
QUINIDINE	4	ABCB1, SCN1A, SCN2A, SCN3A
FELODIPINE	4	ABCB1, SCN1A, SCN2A, SCN3A
PHENYTOIN	4	SCN1A, SCN2A, SCN3A
QUININE	4	ABCB1, SCN1A, SCN2A, SCN3A
NISOLDIPINE	4	ABCB1, SCN1A, SCN2A, SCN3A
NIFEDIPINE	4	SCN1A, SCN2A, SCN3A
PRAZOSIN	4	SCN1A, SCN2A, SCN3A
DILTIAZEM	4	ABCB1, SCN1A, SCN2A, SCN3A
PRENYLAMINE	4	SCN1A, SCN2A, SCN3A
COCAINE	4	SCN1A, SCN2A, SCN3A
TRIFLUOPERAZINE	4	ABCB1, SCN1A, SCN2A, SCN3A
CINNARIZINE	4	SCN1A, SCN2A, SCN3A
THIORIDAZINE	4	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)	13	SCN1A, SCN2A, SCN3A, VRK2, CACNA1H, CACNB4, CASR, ABCB1, GABRA1, GABRA2 (+3 more)
B	Phased (≥1) drug, not yet approved	2	GRIK1, KCNN2
C	Druggable family + PDB, no drug	4	TIMP2, USP25, PNPO, ABCA3
D	Druggable family + AlphaFold only, no drug	1	ADGRV1
E	Difficult family or no structure, no drug	17	SHROOM4, ATXN1, STAT4, BCL11A, ANTKMT, KCNIP1, RAB11FIP3, RBFOX1, CHTF18, FANCL (+7 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SHROOM4	0	—
ATXN1	0	—
STAT4	20	—
TIMP2	0	—
USP25	19	—
BCL11A	0	—
ANTKMT	0	—
KCNIP1	0	—
RAB11FIP3	0	—
ADGRV1	0	—
RBFOX1	0	—
CHTF18	1	—
FANCL	0	—
CALML6	0	—
TTC21B	0	—
RBFOX3	0	—
PNPO	2	—
C1QTNF8	0	—
ABCA3	0	—
ANKRD65	0	—
ARL5A	0	—
PCDH7	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 21.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	13
PHASE3	4
PHASE4	2
PHASE2/PHASE3	1
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03590197	PHASE4	COMPLETED	Effect of Melatonin on Seizure Outcome, Neuronal Damage and Quality of Life in Patients With Generalized Epilepsy
NCT03940326	PHASE4	COMPLETED	Levetiracetam Versus Valproate in Idiopathic Generalized Tonic-clonic Seizures
NCT05147571	PHASE3	ACTIVE_NOT_RECRUITING	RNS System NAUTILUS Study
NCT00150735	PHASE3	COMPLETED	Monotherapy With Levetiracetam in Newly Diagnosed Patients Suffering From Epilepsy
NCT00150748	PHASE3	COMPLETED	Long Term Follow up Treatment With Levetiracetam in Subjects of 4 Years and Older With Generalized Epilepsy
NCT03678753	PHASE3	COMPLETED	Randomized, Double-Blind Study to Evaluate Efficacy and Safety of Cenobamate Adjunctive Therapy in PGTC Seizures
NCT06425159	PHASE2/PHASE3	TERMINATED	A Study to Determine if BHV-7000 is Effective and Safe in Adults With Idiopathic Generalized Epilepsy With Generalized Tonic-clonic Seizures
NCT06908356	PHASE2	RECRUITING	An Open Label Trial to Evaluate the Efficacy and Safety of PRAX-628 in Adults With Focal Onset or Tonic-Clonic Seizures
NCT05374928	Not specified	ACTIVE_NOT_RECRUITING	Human Epilepsy Project 3
NCT06388174	Not specified	RECRUITING	Idiopathic Generalized Epilepsy Syndromes
NCT00001325	Not specified	COMPLETED	Metabolic Abnormalities in Children With Epilepsy
NCT00916903	Not specified	TERMINATED	Genetic Disease Gene Identification
NCT01311440	Not specified	COMPLETED	Modified Atkins Diet Treatment for Adults With Drug-resistant Epilepsy
NCT01432821	Not specified	COMPLETED	Blinking and Yawning in Epilepsy: The Role of Dopamine
NCT03368469	Not specified	WITHDRAWN	Transcranial Direct Current Stimulation (tDCS) in Children and Adolescents With Epilepsy and Depression
NCT03457961	Not specified	UNKNOWN	Post-market Study of AMPA Receptor Antagonists for Epilepsy Patients in Hong Kong
NCT03955432	Not specified	TERMINATED	Long-term Cardiac Monitoring in Epilepsy
NCT04252846	Not specified	COMPLETED	A Study to Investigate Dosage, Effectiveness, and Safety of Perampanel When Used as First Add-on Therapy in Participants >=12 Years With Partial Onset Seizures With or Without Secondary Generalization or With Primary Generalized Tonic-Clonic Seizures Associated With Idiopathic Generalized Epilepsy
NCT04965571	Not specified	COMPLETED	Clinical Features and Outcome of Wilson’s Disease With Generalized Epilepsy in Chinese Patients
NCT05530109	Not specified	TERMINATED	Study of Attentional Disorders in Patients Suffering From Idiopathic Generalized Epilepsy.
NCT06797791	Not specified	COMPLETED	Assessment of Multifocal Continuous Theta Burst Transcranial Magnetic Stimulation (cTBS) Effects in Generalized Epilepsy Patients.

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
LEVETIRACETAM	4	3
PERAMPANEL	4	2
VALPROIC ACID	4	2
CENOBAMATE	4	1
MELATONIN	4	1
ETIRACETAM	2	3
LEVITIRACETAM	0	3