Focal epilepsy

Summary

Focal epilepsy (MONDO:0005384) is a disease (an umbrella term covering 9 Mondo subtypes) with 27 cohort genes (22 GWAS associations across 20 studies) and 97 clinical trials. The dominant Reactome pathway is Interaction between L1 and Ankyrins (5 cohort genes). Top therapeutic interventions include lacosamide, cenobamate, and eslicarbazepine acetate.

At a glance

• Umbrella term: 9 Mondo subtypes
• Cohort genes: 27
• GWAS associations: 22
• ClinVar variants: 23
• Clinical trials: 97

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	focal epilepsy
Mondo ID	MONDO:0005384
EFO	EFO:0004263
MeSH	D004828
DOID	DOID:2234
NCIT	C122812
SNOMED CT	230381009
UMLS	C0014547
MedGen	41836
Is cancer (heuristic)	no

Also known as: focal epilepsy · partial epilepsy

Data availability: 23 ClinVar variants · 22 GWAS associations (20 studies) · 1 GenCC gene-disease record · 89 cell lines.

Disease family

An umbrella term covering 9 Mondo subtypes.

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

Related subtypes (12): extratemporal 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

Subtypes (9): frontal lobe epilepsy, simple partial epilepsy, complex partial epilepsy, partial motor epilepsy, partial sensory epilepsy, familial partial epilepsy, combined generalized and focal epilepsy, variable-age onset focal epilepsy syndrome, childhood-onset self-limited focal epilepsy syndrome

Genetics & variants

GWAS landscape

22 GWAS associations across 20 studies. Top hits map to 11 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs1991545	1e-11	SLC33A1	A	6.78
rs12554609	1e-09	ASS1	?	2.06
rs1318322	7e-09	COX6A1P3 - TBC1D32	G	5.8
rs2212656	7e-09	SCN1A-AS1, SCN1A	A	5.78
chrX:73537149	2e-08		?	1.04
chr19:5961503	2e-08		?	2.25
rs58069848	4e-08	RNU6-440P - FZD7	?	2.02
chrX:51313775	4e-08		?	1.05
chr18:42004210	5e-08		?	1.68
rs12499431	6e-08	SMARCA5	?	2.3
rs74943466	6e-08	CLMP	?
rs12987787	1e-07	SCN1A-AS1, SCN1A	T	1.12
rs346291	3e-07	LINC01621	?	1.2
rs2601828	1e-06	ADCY9	A	1.12
RANBP3	1e-06		?
ASS1	1e-06		?
MAP2K4P1	1e-06		?
rs2172802	3e-06	ADGRL3	?
rs2841498	4e-06	UBE2V1P10 - STK33P1	?
rs1490157	5e-06	ZNF385D	?	1.2
rs2475335	9e-06	PTPRD	?

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90271610	International League Against Epilepsy Consortium on Complex Epilepsies	2023	14,939	42,436	GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture.
GCST90271613	International League Against Epilepsy Consortium on Complex Epilepsies	2023	14,939	42,436	GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture.
GCST007352	International League Against Epilepsy Consortium on Complex Epilepsies	2018	9,095	24,218	Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies.
GCST90271619	International League Against Epilepsy Consortium on Complex Epilepsies	2023	5,778	42,436	GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture.
GCST90271620	International League Against Epilepsy Consortium on Complex Epilepsies	2023	4,213	42,436	GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture.
GCST90477557	Verma A	2024	3,906	444,763	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST000691	Kasperaviciute D	2010	3,445	6,935	Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study.
GCST007351	International League Against Epilepsy Consortium on Complex Epilepsies	2018	2,751	24,218	Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies.
GCST007349	International League Against Epilepsy Consortium on Complex Epilepsies	2018	2,660	24,218	Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies.
GCST90651760	Liu TY	2025	1,759	218,635	Diversity and longitudinal records: Genetic architecture of disease associations and polygenic risk in the Taiwanese Han population.

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	0
Tier 4: intronic/intergenic	21

MAF distribution

Bucket	Variants
common (>=0.05)	11
low_freq (0.01-0.05)	1
rare (<0.01)	0
unknown	9

Functional consequences

Consequence	Count
intron_variant	11
unknown	7
intergenic_variant	2
non_coding_transcript_exon_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs1991545	3	155834522	G>A	0.04	intron_variant	SLC33A1	1e-11	Tier 4: intronic/intergenic
rs12554609	9	130447940	T>G	0.05	intron_variant	ASS1	1e-09	Tier 4: intronic/intergenic
rs1318322	6	121013624	A>G	0.14	intergenic_variant	COX6A1P3 - TBC1D32	7e-09	Tier 4: intronic/intergenic
rs2212656	2	166144333	C>A,T	0.26	intron_variant	SCN1A-AS1, SCN1A	7e-09	Tier 4: intronic/intergenic
chrX:73537149							2e-08	Tier 4: intronic/intergenic
chr19:5961503							2e-08	Tier 4: intronic/intergenic
rs58069848	2	201988068	C>G,T	0.05	intron_variant	RNU6-440P - FZD7	4e-08	Tier 4: intronic/intergenic
chrX:51313775							4e-08	Tier 4: intronic/intergenic
chr18:42004210							5e-08	Tier 4: intronic/intergenic
rs12499431	4	143542079	T>A,C,G		intron_variant	SMARCA5	6e-08	Tier 4: intronic/intergenic
rs74943466	11	123175553	G>T		intron_variant	CLMP	6e-08	Tier 4: intronic/intergenic
rs12987787	2	166001881	T>C,G	0.21	intron_variant	SCN1A-AS1, SCN1A	1e-07	Tier 4: intronic/intergenic
rs346291	6	79855119	C>T	0.366	non_coding_transcript_exon_variant	LINC01621	3e-07	Tier 4: intronic/intergenic
rs2601828	16	4053870	T>A,C,G	0.222	intron_variant	ADCY9	1e-06	Tier 4: intronic/intergenic
RANBP3							1e-06	Tier 4: intronic/intergenic
ASS1							1e-06	Tier 4: intronic/intergenic
MAP2K4P1							1e-06	Tier 4: intronic/intergenic
rs2172802	4	61587491	A>G	0.05	intron_variant	ADGRL3	3e-06	Tier 4: intronic/intergenic
rs2841498	9	85315130	A>C,G,T	0.05	intergenic_variant	UBE2V1P10 - STK33P1	4e-06	Tier 4: intronic/intergenic
rs1490157	3	21677754	C>T	0.261	intron_variant	ZNF385D	5e-06	Tier 4: intronic/intergenic
rs2475335	9	10260263	C>A,G,T	0.05	intron_variant	PTPRD	9e-06	Tier 4: intronic/intergenic

ClinVar germline variants

23 retrieved; paginated sample, class counts are floors:

6 uncertain significance, 6 likely pathogenic, 5 conflicting classifications of pathogenicity, 4 pathogenic/likely pathogenic, 1 pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2504606	NM_001127222.2(CACNA1A):c.185A>G (p.Tyr62Cys)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
375523	NM_001323289.2(CDKL5):c.2641C>T (p.Gln881Ter)	CDKL5	Pathogenic	criteria provided, single submitter
68553	NM_001165963.4(SCN1A):c.4786C>T (p.Arg1596Cys)	LOC102724058	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
68559	NM_001165963.4(SCN1A):c.4970G>A (p.Arg1657His)	LOC102724058	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
207380	NM_001130438.3(SPTAN1):c.6899ACCAGCTGG[1] (p.2300DQL[1])	SPTAN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2446050	NM_001242896.3(DEPDC5):c.3805+1G>A	DEPDC5	Likely pathogenic	criteria provided, single submitter
4076967	NM_001242896.3(DEPDC5):c.279+1G>T	DEPDC5	Likely pathogenic	criteria provided, single submitter
375525	NM_001110792.2(MECP2):c.951G>T (p.Lys317Asn)	MECP2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
183319	NM_002508.3(NID1):c.3385+1G>A	NID1	Likely pathogenic	no assertion criteria provided
375507	NM_001040142.2(SCN2A):c.571T>G (p.Trp191Gly)	SCN2A	Likely pathogenic	criteria provided, single submitter
208672	NM_130811.4(SNAP25):c.142G>T (p.Val48Phe)	SNAP25	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1507278	NM_001242896.3(DEPDC5):c.1838A>G (p.Asn613Ser)	DEPDC5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
205679	NM_001134407.3(GRIN2A):c.3827C>G (p.Ala1276Gly)	GRIN2A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
129360	NM_020822.3(KCNT1):c.2882G>A (p.Arg961His)	KCNT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
68550	NM_001165963.4(SCN1A):c.4628T>C (p.Phe1543Ser)	LOC102724058	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
130252	NM_001330260.2(SCN8A):c.5630A>G (p.Asn1877Ser)	SCN8A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
375538	NM_021098.3(CACNA1H):c.1546C>T (p.His516Tyr)	CACNA1H	Uncertain significance	criteria provided, single submitter
1303653	NM_001242896.3(DEPDC5):c.4748G>A (p.Arg1583His)	DEPDC5	Uncertain significance	criteria provided, multiple submitters, no conflicts
2305883	NM_001242896.3(DEPDC5):c.1021G>T (p.Gly341Cys)	DEPDC5	Uncertain significance	criteria provided, multiple submitters, no conflicts
3779229	NM_001242896.3(DEPDC5):c.4493A>G (p.Asn1498Ser)	DEPDC5	Uncertain significance	criteria provided, single submitter
807199	NM_000810.4(GABRA5):c.713G>A (p.Ser238Asn)	GABRA5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1500544	NM_001077350.3(NPRL3):c.1322C>T (p.Thr441Met)	HBA-LCR	Uncertain significance	criteria provided, multiple submitters, no conflicts
414462	NM_001242896.3(DEPDC5):c.2135C>T (p.Ser712Phe)	DEPDC5	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 69 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 3

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

Gene	HGNC	Evidence routes
SCN2A	SCN2A	GWAS, Orphanet
SCN1A	SCN1A	GWAS, Orphanet
SCN3A	SCN3A	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
CLASP1	Limited	Autosomal dominant	focal epilepsy	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
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
SCN3A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
SCN3A	Orphanet:98820	Familial focal epilepsy with variable foci
SCN8A	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
SCN8A	Orphanet:306	Self-limited infantile epilepsy
SCN8A	Orphanet:352582	Familial infantile myoclonic epilepsy
SCN8A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
SNAP25	Orphanet:98914	Presynaptic congenital myasthenic syndromes
SPTAN1	Orphanet:697160	Infantile epileptic spasms syndrome
CDKL5	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
CDKL5	Orphanet:3095	Atypical Rett syndrome
CDKL5	Orphanet:505652	CDKL5-deficiency disorder
CDKL5	Orphanet:697160	Infantile epileptic spasms syndrome
CACNA1A	Orphanet:2131	Alternating hemiplegia of childhood
CACNA1A	Orphanet:2382	Lennox-Gastaut syndrome
CACNA1A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
CACNA1A	Orphanet:569	Familial or sporadic hemiplegic migraine
CACNA1A	Orphanet:71518	Benign paroxysmal torticollis of infancy
CACNA1A	Orphanet:97	Familial paroxysmal ataxia
CACNA1A	Orphanet:98758	Spinocerebellar ataxia type 6
CACNA1H	Orphanet:642671	Familial hyperaldosteronism type IV
CACNA1H	Orphanet:64280	Childhood absence epilepsy
ELOVL4	Orphanet:1955	Spinocerebellar ataxia type 34
ELOVL4	Orphanet:352333	Congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome
ELOVL4	Orphanet:827	Stargardt disease
DEPDC5	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
DEPDC5	Orphanet:98784	Sleep-related hypermotor epilepsy
DEPDC5	Orphanet:98820	Familial focal epilepsy with variable foci
KCNT1	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
KCNT1	Orphanet:98784	Sleep-related hypermotor epilepsy
TTC21B	Orphanet:474	Jeune syndrome
TTC21B	Orphanet:93591	Infantile nephronophthisis
GABRA5	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
GJA1	Orphanet:1010	Autosomal dominant palmoplantar keratoderma and congenital alopecia
GJA1	Orphanet:1522	Craniometaphyseal dysplasia
GJA1	Orphanet:2248	Hypoplastic left heart syndrome

Cohort genes → proteins

27 cohort genes, 27 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	13
gwas_and_clinvar	1
multi_evidence	13

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCN2A	HGNC:10588	ENSG00000136531	Q99250	Sodium channel protein type 2 subunit alpha	gwas,clinvar
CLASP1	HGNC:17088	ENSG00000074054	Q7Z460	CLIP-associating protein 1	gencc
SCN1A	HGNC:10585	ENSG00000144285	P35498	Sodium channel protein type 1 subunit alpha	gwas
SCN3A	HGNC:10590	ENSG00000153253	Q9NY46	Sodium channel protein type 3 subunit alpha	gwas
SCN8A	HGNC:10596	ENSG00000196876	Q9UQD0	Sodium channel protein type 8 subunit alpha	clinvar
SNAP25	HGNC:11132	ENSG00000132639	P60880	Synaptosomal-associated protein 25	clinvar
SPTAN1	HGNC:11273	ENSG00000197694	Q13813	Spectrin alpha chain, non-erythrocytic 1	clinvar
CDKL5	HGNC:11411	ENSG00000008086	O76039	Cyclin-dependent kinase-like 5	clinvar
CACNA1A	HGNC:1388	ENSG00000141837	O00555	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	clinvar
CACNA1H	HGNC:1395	ENSG00000196557	O95180	Voltage-dependent T-type calcium channel subunit alpha-1H	clinvar
ELOVL4	HGNC:14415	ENSG00000118402	Q9GZR5	Very long chain fatty acid elongase 4	gwas
SH3BGRL2	HGNC:15567	ENSG00000198478	Q9UJC5	SH3 domain-binding glutamic acid-rich-like protein 2	gwas
DEPDC5	HGNC:18423	ENSG00000100150	O75140	GATOR1 complex protein DEPDC5	clinvar
KCNT1	HGNC:18865	ENSG00000107147	Q5JUK3	Potassium channel subfamily T member 1	clinvar
ADGRL3	HGNC:20974	ENSG00000150471	Q9HAR2	Adhesion G protein-coupled receptor L3	gwas
ADCY9	HGNC:240	ENSG00000162104	O60503	Adenylate cyclase type 9	gwas
TTC21B	HGNC:25660	ENSG00000123607	Q7Z4L5	Tetratricopeptide repeat protein 21B	gwas
ZNF385D	HGNC:26191	ENSG00000151789	Q9H6B1	Zinc finger protein 385D	gwas
MISO1	HGNC:26434	ENSG00000174928	Q6P1S2	Protein C3orf33	gwas
GABRA5	HGNC:4079	ENSG00000186297	P31644	Gamma-aminobutyric acid receptor subunit alpha-5	clinvar
GJA1	HGNC:4274	ENSG00000152661	P17302	Gap junction alpha-1 protein	gwas
GRIN2A	HGNC:4585	ENSG00000183454	Q12879	Glutamate receptor ionotropic, NMDA 2A	clinvar
KCNAB1	HGNC:6228	ENSG00000169282	Q14722	Voltage-gated potassium channel subunit beta-1	gwas
MECP2	HGNC:6990	ENSG00000169057	P51608	Methyl-CpG-binding protein 2	clinvar
NID1	HGNC:7821	ENSG00000116962	P14543	Nidogen-1	clinvar
SLC33A1	HGNC:95	ENSG00000169359	O00400	Acetyl-coenzyme A transporter 1	gwas
PTPRD	HGNC:9668	ENSG00000153707	P23468	Receptor-type tyrosine-protein phosphatase delta	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCN2A	Sodium channel protein type 2 subunit alpha	Mediates the voltage-dependent sodium ion permeability of excitable membranes.
CLASP1	CLIP-associating protein 1	Microtubule plus-end tracking protein that promotes the stabilization of dynamic microtubules.
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.
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.
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…
SNAP25	Synaptosomal-associated protein 25	t-SNARE involved in the molecular regulation of neurotransmitter release.
SPTAN1	Spectrin alpha chain, non-erythrocytic 1	Fodrin, which seems to be involved in secretion, interacts with calmodulin in a calcium-dependent manner and is thus candidate for the calcium-dependent movement of the cytoskeleton at the membrane.
CDKL5	Cyclin-dependent kinase-like 5	Mediates phosphorylation of MECP2.
CACNA1A	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene exp…
CACNA1H	Voltage-dependent T-type calcium channel subunit alpha-1H	Voltage-sensitive calcium channel that gives rise to T-type calcium currents.
ELOVL4	Very long chain fatty acid elongase 4	Catalyzes the first and rate-limiting reaction of the four reactions that constitute the long-chain fatty acids elongation cycle.
DEPDC5	GATOR1 complex protein DEPDC5	As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway.
KCNT1	Potassium channel subfamily T member 1	Sodium-activated K(+) channel.
ADGRL3	Adhesion G protein-coupled receptor L3	Orphan adhesion G-protein coupled receptor (aGPCR), which mediates synapse specificity.
ADCY9	Adenylate cyclase type 9	Adenylyl cyclase that catalyzes the formation of the signaling molecule cAMP in response to activation of G protein-coupled receptors.
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).
MISO1	Protein C3orf33	Secreted protein may play a role in transcription regulation via the MAPK3/MAPK1 pathway through an unidentified receptor on the plasma membrane.
GABRA5	Gamma-aminobutyric acid receptor subunit alpha-5	Alpha subunit of the heteropentameric ligand-gated chloride channel gated by gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain.
GJA1	Gap junction alpha-1 protein	Structural component of the gap junction, a specialized intercellular structure consisting of a cluster of closely packed pairs of transmembrane channels, the connexons, that allow passage of small molecules and electrical signals between…
GRIN2A	Glutamate receptor ionotropic, NMDA 2A	Component of N-methyl-D-aspartate (NMDA) receptors (NMDARs) that function as heterotetrameric, ligand-gated cation channels with high calcium permeability and voltage-dependent block by Mg(2+).
KCNAB1	Voltage-gated potassium channel subunit beta-1	Regulatory subunit of the voltage-gated potassium (Kv) Shaker channels composed of pore-forming and potassium-conducting alpha subunits and of regulatory beta subunits.
MECP2	Methyl-CpG-binding protein 2	Chromosomal protein that binds to methylated DNA.
NID1	Nidogen-1	Sulfated glycoprotein widely distributed in basement membranes and tightly associated with laminin.
SLC33A1	Acetyl-coenzyme A transporter 1	Acetyl-CoA transporter that mediates active acetyl-CoA import through the endoplasmic reticulum (ER) membrane into the ER lumen where specific ER-based acetyl-CoA:lysine acetyltransferases are responsible for the acetylation of ER-based pr…
PTPRD	Receptor-type tyrosine-protein phosphatase delta	Can bidirectionally induce pre- and post-synaptic differentiation of neurons by mediating interaction with IL1RAP and IL1RAPL1 trans-synaptically.

Protein-family classification

Druggable: 12 · Difficult: 3 · Unknown: 12 · Druggable fraction: 0.44

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	8	33.0×	5e-10
Phosphatase	1	3.1×	0.787
Transporter	1	2.9×	0.787
Scaffold/PPI	2	1.3×	0.912
Kinase	1	1.0×	0.912
GPCR	1	0.9×	0.912
Other/Unknown	12	0.8×	0.969
Transcription factor	1	0.3×	0.969

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCN2A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
CLASP1	Other/Unknown	no		ARM-like, ARM-type_fold, HEAT_type_2
SCN1A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a1su
SCN3A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_trans_assoc_dom
SCN8A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
SNAP25	Other/Unknown	no		T_SNARE_dom, SNAP-25_dom, SNAP-25_N_SNARE_chord
SPTAN1	Scaffold/PPI	no		SH3_domain, Spectrin_repeat, EF_hand_dom
CDKL5	Kinase	yes	2.7.11.22	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
CACNA1A	Ion channel	yes		VDCCAlpha1, CACNA1A, Ion_trans_dom
CACNA1H	Ion channel	yes		VDCC_T_a1, Ion_trans_dom, Volt_channel_dom_sf
ELOVL4	Other/Unknown	no		ELO_fam, ELO_CS, ELOVL4
SH3BGRL2	Scaffold/PPI	no		Glut_rich_SH3-bd, Thioredoxin-like_sf, SH3BGR
DEPDC5	Other/Unknown	no		DEP_dom, IML1, WH-like_DNA-bd_sf
KCNT1	Ion channel	yes		RCK_N, K_chnl_BK_asu, K_chnl_dom
ADGRL3	GPCR	yes		GPS, GPCR_2_secretin-like, Lectin_gal-bd_dom
ADCY9	Other/Unknown	no		A/G_cyclase, A/G_cyclase_CS, Nucleotide_cyclase
TTC21B	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, TTC21A/TTC21B
ZNF385D	Transcription factor	no		Matrin/U1-like-C_Znf_C2H2, Znf_C2H2_type, Znf_C2H2_sf
MISO1	Other/Unknown	no		SNase_OB-fold_sf, C3orf33-like
GABRA5	Other/Unknown	no		GABAAa_rcpt, GABBAa5_rcpt, GABAA/Glycine_rcpt
GJA1	Other/Unknown	no		Connexin, Connexin43, Connexin_N
GRIN2A	Other/Unknown	no		Iontro_rcpt_C, Iono_Glu_rcpt_met, ANF_lig-bd_rcpt
KCNAB1	Ion channel	yes		K_chnl_volt-dep_bsu_KCNAB-rel, K_chnl_volt-dep_bsu_KCNAB1, K_chnl_volt-dep_bsu_KCNAB
MECP2	Other/Unknown	no		Methyl_CpG_DNA-bd, DNA-bd_dom_sf, Me_CpG-bd_MeCP2
NID1	Other/Unknown	no		LDLR_classB_rpt, EGF-type_Asp/Asn_hydroxyl_site, Thyroglobulin_1
SLC33A1	Transporter	yes		AmpG_permease/AT-1, AcetylCoA_trans_1-like, MFS_trans_sf
PTPRD	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, Tyr_Pase_cat

Expression context

Cohort genes with no expression data: 0.

27 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)	27
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	5
cerebellar hemisphere	5
middle temporal gyrus	4
cortical plate	4
cerebellar cortex	4
right hemisphere of cerebellum	4
calcaneal tendon	2
dorsal motor nucleus of vagus nerve	2
endothelial cell	2
frontal pole	2
paraflocculus	2
hair follicle	2
Brodmann (1909) area 10	2
lateral globus pallidus	2
cerebellar vermis	1
lateral nuclear group of thalamus	1
primary visual cortex	1
postcentral gyrus	1
cerebellum	1
pons	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCN2A	187	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, cerebellar vermis
CLASP1	286	ubiquitous	marker	cortical plate, calcaneal tendon, dorsal motor nucleus of vagus nerve
SCN1A	154	tissue_specific	marker	Brodmann (1909) area 23, lateral nuclear group of thalamus, primary visual cortex
SCN3A	221	broad	marker	endothelial cell, cortical plate, middle temporal gyrus
SCN8A	194	ubiquitous	marker	Brodmann (1909) area 23, middle temporal gyrus, postcentral gyrus
SNAP25	220	broad	marker	pons, cerebellar cortex, cerebellum
SPTAN1	293	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
CDKL5	257	ubiquitous	marker	frontal pole, Brodmann (1909) area 23, cortical plate
CACNA1A	237	broad	marker	cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex
CACNA1H	166	broad	marker	lower esophagus muscularis layer, muscle layer of sigmoid colon, lower esophagus
ELOVL4	228	ubiquitous	marker	upper leg skin, upper arm skin, mammalian vulva
SH3BGRL2	249	ubiquitous	marker	parotid gland, ileal mucosa, esophagus squamous epithelium
DEPDC5	236	ubiquitous	marker	paraflocculus, frontal pole, middle frontal gyrus
KCNT1	153	tissue_specific	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
ADGRL3	246	broad	marker	adrenal tissue, hair follicle, saphenous vein
ADCY9	296	ubiquitous	marker	secondary oocyte, choroid plexus epithelium, vastus lateralis
TTC21B	179	ubiquitous	marker	right uterine tube, calcaneal tendon, cerebellar hemisphere
ZNF385D	221	broad	marker	descending thoracic aorta, ascending aorta, thoracic aorta
MISO1	133	ubiquitous	marker	right adrenal gland, right adrenal gland cortex, left adrenal gland
GABRA5	141	broad	marker	nucleus accumbens, prefrontal cortex, Brodmann (1909) area 10
GJA1	292	ubiquitous	marker	lateral globus pallidus, dorsal motor nucleus of vagus nerve, hair follicle
GRIN2A	199	broad	marker	Brodmann (1909) area 23, endothelial cell, middle temporal gyrus
KCNAB1	263	broad	marker	blood vessel layer, lateral globus pallidus, popliteal artery
MECP2	277	ubiquitous	marker	paraflocculus, Brodmann (1909) area 10, sural nerve
NID1	262	ubiquitous	marker	stromal cell of endometrium, mucosa of stomach, lower lobe of lung
SLC33A1	278	ubiquitous	marker	corpus epididymis, body of pancreas, islet of Langerhans
PTPRD	160	broad	marker	cortical plate, right hemisphere of cerebellum, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 13.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MECP2	5,688
GJA1	4,942
GRIN2A	3,146
SPTAN1	3,083
PTPRD	3,052
SCN2A	2,810
SCN1A	2,287
SLC33A1	2,262
SCN8A	2,120
ELOVL4	2,115

Intra-cohort edges

A	B	Sources
CDKL5	KCNT1	string_interaction
CDKL5	MECP2	string_interaction
CDKL5	SCN1A	string_interaction
CDKL5	SCN2A	string_interaction
DEPDC5	KCNT1	string_interaction
GABRA5	MECP2	string_interaction
GABRA5	SCN1A	string_interaction
GJA1	SCN3A	string_interaction
KCNT1	SCN1A	string_interaction
KCNT1	SCN2A	string_interaction
KCNT1	SCN8A	string_interaction
SCN1A	SCN2A	biogrid_interaction, string_interaction
SCN2A	SCN3A	intact

Structural data

PDB: 22 · AlphaFold-only: 5 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GRIN2A	Q12879	37
GABRA5	P31644	23
GJA1	P17302	19
SNAP25	P60880	14
DEPDC5	O75140	11
MECP2	P51608	9
PTPRD	P23468	8
SCN8A	Q9UQD0	7
SPTAN1	Q13813	7
ADGRL3	Q9HAR2	7
KCNT1	Q5JUK3	6
ADCY9	O60503	6
SCN2A	Q99250	5
CACNA1H	O95180	5
CACNA1A	O00555	4
CLASP1	Q7Z460	3
CDKL5	O76039	3
TTC21B	Q7Z4L5	3
SCN3A	Q9NY46	2
SLC33A1	O00400	2
SCN1A	P35498	1
SH3BGRL2	Q9UJC5	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KCNAB1	Q14722	87.13
ELOVL4	Q9GZR5	84.53
NID1	P14543	78.50
MISO1	Q6P1S2	67.88
ZNF385D	Q9H6B1	62.68

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 162. Enrichment computed across 27 evidence-associated genes (21 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 21 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	5	87.7×	3e-07	SCN2A, SCN1A, SCN3A, SCN8A, SPTAN1
Phase 0 - rapid depolarisation	4	65.9×	3e-05	SCN2A, SCN1A, SCN3A, SCN8A
L1CAM interactions	5	28.6×	4e-05	SCN2A, SCN1A, SCN3A, SCN8A, SPTAN1
Muscle contraction	5	18.4×	2e-04	SCN2A, SCN1A, SCN3A, SCN8A, CACNA1H
Axon guidance	6	12.9×	2e-04	SCN2A, SCN1A, SCN3A, SCN8A, SPTAN1, CACNA1H
Nervous system development	6	12.3×	2e-04	SCN2A, SCN1A, SCN3A, SCN8A, SPTAN1, CACNA1H
Cardiac conduction	4	20.7×	8e-04	SCN2A, SCN1A, SCN3A, SCN8A
Sensory Perception	4	18.1×	0.001	SCN2A, SCN3A, SNAP25, SPTAN1
Integration of energy metabolism	3	25.1×	0.004	SNAP25, CACNA1A, ADCY9
Mechanical load activates signaling by PIEZO1 and integrins in osteocytes	2	64.0×	0.007	CACNA1H, GJA1
MECP2 regulates neuronal receptors and channels	2	57.2×	0.008	GRIN2A, MECP2
Synaptic adhesion-like molecules	2	51.8×	0.009	GRIN2A, PTPRD
Neuronal System	4	8.4×	0.014	SNAP25, CACNA1A, ADCY9, KCNAB1
Defective SLC33A1 causes spastic paraplegia 42 (SPG42)	1	543.8×	0.019	SLC33A1
Loss of MECP2 binding ability to 5hmC-DNA	1	543.8×	0.019	MECP2
Sensory perception of taste	2	32.0×	0.019	SCN2A, SCN3A
GABA receptor activation	2	30.2×	0.019	ADCY9, GABRA5
Sensory processing of sound	2	29.4×	0.019	SNAP25, SPTAN1
Sensory perception of sweet, bitter, and umami (glutamate) taste	2	26.5×	0.020	SCN2A, SCN3A
Transmission across Chemical Synapses	3	10.9×	0.020	SNAP25, CACNA1A, ADCY9
Developmental Biology	6	4.1×	0.020	SCN2A, SCN1A, SCN3A, SCN8A, SPTAN1, CACNA1H
NCAM signaling for neurite out-growth	2	25.9×	0.020	SPTAN1, CACNA1H
Cellular responses to mechanical stimuli	2	24.7×	0.020	CACNA1H, ADCY9
Regulation of insulin secretion	2	20.9×	0.027	SNAP25, CACNA1A
Oligomerization of connexins into connexons	1	181.3×	0.030	GJA1
Transport of connexins along the secretory pathway	1	181.3×	0.030	GJA1
Regulation of gap junction activity	1	181.3×	0.030	GJA1
Toxicity of botulinum toxin type C (botC)	1	181.3×	0.030	SNAP25
Toxicity of botulinum toxin type E (botE)	1	181.3×	0.030	SNAP25
MECP2 regulates transcription of genes involved in GABA signaling	1	181.3×	0.030	MECP2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 25 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cardiac muscle cell action potential involved in contraction	4	112.3×	1e-05	SCN2A, SCN1A, SCN3A, SCN8A
sodium ion transmembrane transport	5	40.6×	2e-05	SCN2A, SCN1A, SCN3A, SCN8A, GRIN2A
sodium ion transport	4	43.5×	2e-04	SCN2A, SCN1A, SCN3A, SCN8A
membrane depolarization during action potential	2	134.8×	0.005	SCN1A, SCN3A
long-term synaptic potentiation	3	33.7×	0.005	SNAP25, GRIN2A, MECP2
startle response	2	89.9×	0.009	GRIN2A, MECP2
modulation of chemical synaptic transmission	3	22.0×	0.012	CDKL5, CACNA1A, PTPRD
ventricular system development	2	67.4×	0.013	TTC21B, MECP2
acetyl-CoA transmembrane transport	1	674.1×	0.020	SLC33A1
catecholamine secretion	1	674.1×	0.020	MECP2
microtubule-based transport	1	674.1×	0.020	GJA1
trans-synaptic signaling by BDNF	1	674.1×	0.020	MECP2
positive regulation of mesodermal cell differentiation	1	674.1×	0.020	GJA1
calcium ion import across plasma membrane	2	43.5×	0.020	CACNA1A, CACNA1H
basement membrane organization	2	40.9×	0.020	CLASP1, NID1
associative learning	2	38.5×	0.020	SNAP25, GABRA5
neuronal action potential	2	38.5×	0.020	SCN2A, SCN1A
excitatory postsynaptic potential	2	35.5×	0.020	GRIN2A, MECP2
behavioral fear response	2	34.6×	0.020	GABRA5, MECP2
cellular response to amyloid-beta	2	31.4×	0.024	CACNA1A, GJA1
sensory perception of pain	2	30.0×	0.025	GRIN2A, MECP2
intrinsic apoptotic signaling pathway in response to osmotic stress	1	337.0×	0.030	SCN2A
cardiolipin metabolic process	1	337.0×	0.030	MECP2
negative regulation of gonadotropin secretion	1	337.0×	0.030	GJA1
regulation of intraciliary retrograde transport	1	337.0×	0.030	TTC21B
visual learning	2	24.5×	0.030	GRIN2A, MECP2
nervous system process involved in regulation of systemic arterial blood pressure	1	224.7×	0.032	MECP2
biogenic amine metabolic process	1	224.7×	0.032	MECP2
negative regulation of microtubule polymerization or depolymerization	1	224.7×	0.032	CLASP1
directional locomotion	1	224.7×	0.032	GRIN2A

Therapeutics

Drugs indicated for this disease

6 approved, 7 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Carbamazepine	Approved (phase 4)
Lacosamide	Approved (phase 4)
Lamotrigine	Approved (phase 4)
Perampanel	Approved (phase 4)
Vigabatrin	Approved (phase 4)
Zonisamide	Approved (phase 4)
Cenobamate	Phase 3 (in late-stage trials)
Eslicarbazepine Acetate	Phase 3 (in late-stage trials)
Gabapentin	Phase 3 (in late-stage trials)
Levetiracetam	Phase 3 (in late-stage trials)
Oxcarbazepine	Phase 3 (in late-stage trials)
Pregabalin	Phase 3 (in late-stage trials)
Topiramate	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Azetukalner, Ganaxolone, Ibuprofen, Nifedipine, Padsevonil, Seletracetam.

Drug target analysis

Approved (phase 4): 11 · Phase ≥3: 11 · Phased (≥1): 12 · Undrugged: 15

Druggability breadth: 20 of 27 evidence-associated genes (74%) 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
SCN2A	BEPRIDIL
SCN1A	MEXILETINE HYDROCHLORIDE
SCN3A	BEPRIDIL
SCN8A	IMIPRAMINE
CDKL5	FEDRATINIB
CACNA1A	NIMODIPINE
CACNA1H	PIMOZIDE
KCNT1	BEPRIDIL
GABRA5	ENZALUTAMIDE
GJA1	KANAMYCIN
GRIN2A	MEMANTINE HYDROCHLORIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN2A	99	4
SCN1A	94	4
SCN3A	93	4
GRIN2A	37	4
GABRA5	27	4
SCN8A	25	4
CDKL5	14	4
CACNA1H	10	4
CACNA1A	2	4
KCNT1	2	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	KCNT1, SCN1A, SCN2A, SCN3A
DIBUCAINE	4	SCN1A, SCN2A, SCN3A
ARTICAINE	4	SCN1A, SCN2A, SCN3A
BUPIVACAINE	4	SCN1A, SCN2A, SCN3A
IMIPRAMINE	4	SCN1A, SCN2A, SCN3A, SCN8A
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	KCNT1, SCN1A, SCN2A, SCN3A
FELODIPINE	4	SCN1A, SCN2A, SCN3A
PHENYTOIN	4	SCN1A, SCN2A, SCN3A
QUININE	4	SCN1A, SCN2A, SCN3A
NISOLDIPINE	4	SCN1A, SCN2A, SCN3A
NIFEDIPINE	4	SCN1A, SCN2A, SCN3A, SCN8A
PRAZOSIN	4	SCN1A, SCN2A, SCN3A
DILTIAZEM	4	SCN1A, SCN2A, SCN3A, SCN8A
PRENYLAMINE	4	SCN1A, SCN2A, SCN3A
COCAINE	4	SCN1A, SCN2A, SCN3A
TRIFLUOPERAZINE	4	SCN1A, SCN2A, SCN3A
CINNARIZINE	4	SCN1A, SCN2A, SCN3A
THIORIDAZINE	4	SCN1A, SCN2A, SCN3A
ETIDOCAINE	4	SCN1A, SCN2A, SCN3A
CHLORPHENIRAMINE	4	SCN1A, SCN2A, SCN3A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
GABRA5	413	Binding:352, Functional:57, Toxicity:3, ADMET:1
GRIN2A	324	Binding:296, Functional:23, ADMET:4, Toxicity:1
SCN2A	203	Binding:172, Functional:20, ADMET:10, Toxicity:1
SCN8A	173	Binding:148, Functional:16, ADMET:7, Toxicity:2
SCN1A	149	Binding:115, Functional:18, ADMET:14, Toxicity:2
CACNA1H	124	Binding:102, Functional:17, ADMET:4, Toxicity:1
SCN3A	102	Binding:79, Functional:18, ADMET:4, Toxicity:1
CDKL5	74	Binding:74
KCNT1	24	Binding:24
CACNA1A	19	Binding:18, Functional:1
ADCY9	18	Binding:16, Functional:2
CLASP1	10	Binding:10
SPTAN1	7	Binding:7
KCNAB1	7	Binding:7
GJA1	4	Binding:4
SLC33A1	2	Binding:2
ELOVL4	1	Binding:1
MECP2	1	Binding:1
PTPRD	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CDKL5	2.7.11.22	cyclin-dependent kinase
PTPRD	3.1.3.48	protein-tyrosine-phosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN2A	203
SCN1A	149
SCN3A	102
SCN8A	173
CACNA1H	124
GABRA5	413
GRIN2A	324

Pharmacogenomics

Cohort genes with a PharmGKB record: 27; 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)
BEPRIDIL	4	KCNT1, SCN1A, SCN2A, SCN3A
DIBUCAINE	4	SCN1A, SCN2A, SCN3A
ARTICAINE	4	SCN1A, SCN2A, SCN3A
BUPIVACAINE	4	SCN1A, SCN2A, SCN3A
IMIPRAMINE	4	SCN1A, SCN2A, SCN3A, SCN8A
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	KCNT1, SCN1A, SCN2A, SCN3A
FELODIPINE	4	SCN1A, SCN2A, SCN3A
PHENYTOIN	4	SCN1A, SCN2A, SCN3A
QUININE	4	SCN1A, SCN2A, SCN3A
NISOLDIPINE	4	SCN1A, SCN2A, SCN3A
NIFEDIPINE	4	SCN1A, SCN2A, SCN3A, SCN8A
PRAZOSIN	4	SCN1A, SCN2A, SCN3A
DILTIAZEM	4	SCN1A, SCN2A, SCN3A, SCN8A
PRENYLAMINE	4	SCN1A, SCN2A, SCN3A
COCAINE	4	SCN1A, SCN2A, SCN3A
TRIFLUOPERAZINE	4	SCN1A, SCN2A, SCN3A
CINNARIZINE	4	SCN1A, SCN2A, SCN3A
THIORIDAZINE	4	SCN1A, SCN2A, SCN3A
ETIDOCAINE	4	SCN1A, SCN2A, SCN3A
CHLORPHENIRAMINE	4	SCN1A, SCN2A, SCN3A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	11	SCN2A, SCN1A, SCN3A, SCN8A, CDKL5, CACNA1A, CACNA1H, KCNT1, GABRA5, GJA1 (+1 more)
B	Phased (≥1) drug, not yet approved	1	SPTAN1
C	Druggable family + PDB, no drug	3	ADGRL3, SLC33A1, PTPRD
D	Druggable family + AlphaFold only, no drug	1	KCNAB1
E	Difficult family or no structure, no drug	11	CLASP1, SNAP25, ELOVL4, SH3BGRL2, DEPDC5, ADCY9, TTC21B, ZNF385D, MISO1, MECP2 (+1 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CLASP1	10	—
SNAP25	0	—
ELOVL4	1	—
SH3BGRL2	0	—
DEPDC5	0	—
ADGRL3	0	—
ADCY9	18	—
TTC21B	0	—
ZNF385D	0	—
MISO1	0	—
KCNAB1	7	—
MECP2	1	—
NID1	0	—
SLC33A1	2	—
PTPRD	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 97.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	44
PHASE3	17
PHASE2	17
PHASE4	10
PHASE1	5
PHASE2/PHASE3	2
PHASE1/PHASE2	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07193277	PHASE4	RECRUITING	Butylphthalide for Cognitive Impairment in Elderly Patients With Focal Epilepsy
NCT00438451	PHASE4	COMPLETED	Study on the Treatment of Elderly Patients With Older and Newer Antiepileptic Drugs
NCT00522418	PHASE4	TERMINATED	Study Comparing Best Medical Practice With or Without VNS Therapy in Pharmacoresistant Partial Epilepsy Patients
NCT00855738	PHASE4	COMPLETED	A Prospective, Observational Study On The Effectiveness Of New Antiepileptic Drugs As First Bitherapy In The Daily Clinical Practice
NCT00955357	PHASE4	COMPLETED	Trial to Assess Lacosamide as the First add-on Anti-epileptic Drug Treatment in Patients With Partial-onset Seizures
NCT01190098	PHASE4	COMPLETED	Randomized Controlled Trial to Assess Effects of Lacosamide on Sleep and Wake in Adults With Focal Epilepsy
NCT01235403	PHASE4	COMPLETED	Trial to Assess Optimized Dosage of Lacosamide as add-on Therapy in Patients With Partial Onset Seizure
NCT02208492	PHASE4	COMPLETED	The Effects on Cognitive Function of Levetiracetam (Keppra®) Compared to Carbamazepine (Tegretol®, Carmazepine®) as Monotherapy for Children With Partial Seizure; A Multicentric Randomized Controlled Study
NCT03607851	PHASE4	COMPLETED	Efficacy and Safety of Rapid Titration Protocols of Lacosamide
NCT05748236	PHASE4	UNKNOWN	The Efficacy and Safety of Lamotrigine Versus Carbamazepine in Focal Epilepsy
NCT05067634	PHASE3	ACTIVE_NOT_RECRUITING	Safety and Efficacy Study of Cenobamate in Pediatric Subjects 2-17 Years of Age With Partial-onset (Focal) Seizures
NCT05718817	PHASE3	ENROLLING_BY_INVITATION	An Open-label Study of XEN1101 in Epilepsy
NCT06132893	PHASE2/PHASE3	RECRUITING	A Study to Determine if BHV-7000 is Effective and Safe in Adults With Refractory Focal Onset Epilepsy
NCT06309966	PHASE2/PHASE3	RECRUITING	Study to Determine if BHV-7000 is Effective and Safe in Adults With Refractory Focal Onset Epilepsy
NCT07505004	PHASE3	RECRUITING	Double-blind, Randomized Clinical Trial Evaluating the Efficacy and Safety of Vormatrigine in Adults With Focal Seizures
NCT07563881	PHASE3	RECRUITING	Study Evaluating the Efficacy and Safety of RAP-219 in Adult Participants With Focal Seizures FOCUS-1
NCT07594119	PHASE3	NOT_YET_RECRUITING	Study Evaluating the Efficacy and Safety of RAP-219 in Adult Participants With Focal Seizures
NCT07594158	PHASE3	RECRUITING	A Study to Evaluate the Safety, Efficacy, and PK of ONO-2017 in Japanese Patients With POS 2 to 17 Year Olds
NCT00391534	PHASE3	TERMINATED	EXTENT: EXtended Tolerability and Efficacy of a Novel Formulation of Oxcarbazepine in a Trial in Partial Epilepsy
NCT00522275	PHASE3	COMPLETED	Determine Safety and Efficacy of Long-term Oral Lacosamide in Patients With Partial Seizures
NCT00655486	PHASE3	COMPLETED	Study to Assess the Long-term Safety of Oral Lacosamide in Subjects With Partial-onset Seizures
NCT00655551	PHASE3	COMPLETED	Safety of Intravenous Lacosamide Dose Followed by Twice Daily Oral Lacosamide in Subjects With Partial-onset Seizures
NCT00908349	PHASE3	COMPLETED	Safety and Tolerability of OXC XR as Adjunctive Therapy in Subjects With Refractory Partial Epilepsy
NCT00957047	PHASE3	COMPLETED	Efficacy and Safety Study of BIA 2-093 in Combination With Other Anti-Epileptic Drugs to Treat Partial Epilepsy
NCT00957372	PHASE3	COMPLETED	Efficacy and Safety of Eslicarbazepine Acetate as Adjunctive Therapy for Refractory Partial Epilepsy
NCT00957684	PHASE3	COMPLETED	Efficacy and Safety of Eslicarbazepine Acetate as Adjunctive Therapy for Refractory Partial Seizures
NCT00988429	PHASE3	COMPLETED	Efficacy and Safety of Eslicarbazepine Acetate (BIA 2-093) as Adjunctive Therapy for Refractory Partial Seizures
NCT02076698	PHASE3	COMPLETED	Deep Brain Stimulation of the Anterior Nucleus of the Thalamus in Epilepsy
NCT02535091	PHASE3	COMPLETED	Safety and Pharmacokinetic Study of YKP3089 as Adjunctive Therapy in Subjects With Partial Onset Seizures
NCT03796962	PHASE2	ACTIVE_NOT_RECRUITING	A Study to Evaluate XEN1101 as Adjunctive Therapy in Focal Epilepsy
NCT06443463	PHASE2	ENROLLING_BY_INVITATION	Long-term Safety and Tolerability of BHV-7000
NCT06612775	PHASE2	NOT_YET_RECRUITING	A Study to Evaluate the Safety, Tolerability, and Efficacy of CB03-154 in Adult Patients With Focal Epilepsy
NCT07219407	PHASE2	RECRUITING	A Long-term Study of the Safety and Effectiveness of RAP-219 in Adults With Focal Onset Seizures
NCT07238868	PHASE2	RECRUITING	An Open-label Study to Evaluate Safety, Tolerability, and Efficacy of CB03-154 in Subjects Diagnosed With Epilepsy
NCT07318870	PHASE2	NOT_YET_RECRUITING	Efficacy of Probenecid on Cluster Seizures During Anti Seizure Medication Withdrawal in Presurgical Focal Epilepsy Video-EEG Monitoring
NCT00465517	PHASE2	COMPLETED	A Randomized, Controlled Trial of Ganaxolone in Adult Uncontrolled Partial-Onset Seizures
NCT00552305	PHASE2	COMPLETED	To Determine Tolerability and Efficacy of Long-term Oral Lacosamide in Patients With Partial Seizures
NCT00982787	PHASE2	WITHDRAWN	Safety and Anticonvulsant Efficacy of Passiflora Incarnata Extract in Patients With Partial Epilepsy
NCT01048255	PHASE2	COMPLETED	Study of VX-765 in Subjects With Treatment-resistant Partial Epilepsy
NCT01281956	PHASE2	TERMINATED	PRX-00023 Therapy in Localization-Related Epilepsy

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
LACOSAMIDE	4	8
CENOBAMATE	4	6
ESLICARBAZEPINE ACETATE	4	4
LAMOTRIGINE	4	3
LEVETIRACETAM	4	3
ESLICARBAZEPINE	4	2
PERAMPANEL	4	2
TIAGABINE	4	2
BUSPIRONE	4	1
CARBAMAZEPINE	4	1
GABAPENTIN	4	1
GANAXOLONE	4	1
OXCARBAZEPINE	4	1
PREGABALIN	4	1
PROBENECID	4	1
TOPIRAMATE	4	1
ZONISAMIDE	4	1
AZETUKALNER	3	2
NALUZOTAN	3	1
RAC-3-N-BUTYLPHTHALIDE	3	1
ETIRACETAM	2	3
BELNACASAN	2	1
LEVITIRACETAM	0	3
CHEMBL249818	0	1