Developmental and epileptic encephalopathy, 1

Summary

Developmental and epileptic encephalopathy, 1 (MONDO:0010632) is a disease caused by ARX (GenCC Strong), with 44 cohort genes. The dominant Reactome pathway is Interaction between L1 and Ankyrins (6 cohort genes).

At a glance

• Causal gene: ARX (GenCC Strong)
• Cohort genes: 44
• ClinVar variants: 2,383

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 1
Mondo ID	MONDO:0010632
OMIM	308350
DOID	DOID:0080468
UMLS	C3463992
MedGen	483052
GARD	0015298
Is cancer (heuristic)	no

Also known as: ARX early infantile epileptic encephalopathy · DEE1 · developmental and epileptic encephalopathy 1, X-linked recessive · early infantile epileptic encephalopathy caused by mutation in ARX · early infantile epileptic encephalopathy caused by mutation in arx · EIEE1 · epileptic encephalopathy, early infantile, 1 · epileptic encephalopathy, early infantile, type 1 · XMESID

Data availability: 2,383 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › infantile spasms › developmental and epileptic encephalopathy, 1

Related subtypes (7): developmental and epileptic encephalopathy, 2, developmental and epileptic encephalopathy, 5, developmental and epileptic encephalopathy, 12, developmental and epileptic encephalopathy, 15, developmental and epileptic encephalopathy, 27, developmental and epileptic encephalopathy, 30, developmental and epileptic encephalopathy, 40

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

278 uncertain significance, 202 likely benign, 38 conflicting classifications of pathogenicity, 35 pathogenic, 16 benign/likely benign, 15 benign, 9 likely pathogenic, 6 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1070790	NM_139058.3(ARX):c.303_323dup (p.Ala109_Ala115dup)	ARX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074175	NM_139058.3(ARX):c.1443dup (p.Gly482fs)	ARX	Pathogenic	criteria provided, single submitter
11188	NM_139058.3(ARX):c.1058C>T (p.Pro353Leu)	ARX	Pathogenic	criteria provided, multiple submitters, no conflicts
11189	NM_139058.3(ARX):c.1449-816_*460del	ARX	Pathogenic	no assertion criteria provided
11192	NM_139058.3(ARX):c.995G>A (p.Arg332His)	ARX	Pathogenic	criteria provided, multiple submitters, no conflicts
11194	NM_139058.3(ARX):c.1187dup (p.Gly397fs)	ARX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11202	NM_139058.3(ARX):c.309_341dup (p.Ala105_Ala115dup)	ARX	Pathogenic	criteria provided, multiple submitters, no conflicts
1299655	NM_139058.3(ARX):c.1472del (p.Leu491fs)	ARX	Pathogenic	criteria provided, multiple submitters, no conflicts
1374869	NM_139058.3(ARX):c.1125G>A (p.Trp375Ter)	ARX	Pathogenic	criteria provided, single submitter
1410535	NM_139058.3(ARX):c.642_645del (p.Pro215fs)	ARX	Pathogenic	criteria provided, single submitter
1434577	NM_139058.3(ARX):c.1120-2A>G	ARX	Pathogenic	criteria provided, single submitter
1494703	NM_139058.3(ARX):c.994C>G (p.Arg332Gly)	ARX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
157739	NM_139058.3(ARX):c.1111C>T (p.Arg371Ter)	ARX	Pathogenic	criteria provided, multiple submitters, no conflicts
157748	NM_139058.3(ARX):c.1465del (p.Ala489fs)	ARX	Pathogenic	criteria provided, single submitter
11186	NM_139058.3(ARX):c.306GGC[17] (p.Ala109_Ala115dup)	LOC109610631	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1381570	NM_016373.4(WWOX):c.1057C>T (p.Gln353Ter)	MAF	Pathogenic	criteria provided, single submitter
1174107	NM_001165963.4(SCN1A):c.126_128delinsCC (p.Lys42fs)	SCN1A	Pathogenic	no assertion criteria provided
1029242	NM_001199107.2(TBC1D24):c.965+2T>C	TBC1D24	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066340	NM_001199107.2(TBC1D24):c.115G>C (p.Ala39Pro)	TBC1D24	Pathogenic	criteria provided, single submitter
1071941	NM_001199107.2(TBC1D24):c.642_793del (p.Trp215fs)	TBC1D24	Pathogenic	criteria provided, multiple submitters, no conflicts
1072207	NM_001199107.2(TBC1D24):c.715del (p.Val239fs)	TBC1D24	Pathogenic	criteria provided, single submitter
133246	NM_001199107.2(TBC1D24):c.533C>T (p.Ser178Leu)	TBC1D24	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1357131	NM_001199107.2(TBC1D24):c.1397del (p.Pro466fs)	TBC1D24	Pathogenic	criteria provided, single submitter
1369893	NM_001199107.2(TBC1D24):c.56del (p.Ile19fs)	TBC1D24	Pathogenic	criteria provided, single submitter
1378399	NM_001199107.2(TBC1D24):c.979A>T (p.Lys327Ter)	TBC1D24	Pathogenic	criteria provided, single submitter
1397090	NM_001199107.2(TBC1D24):c.1540C>T (p.Gln514Ter)	TBC1D24	Pathogenic	criteria provided, single submitter
1402576	NC_000016.9:g.(?2546150)(2550959_?)del	TBC1D24	Pathogenic	criteria provided, single submitter
1451981	NM_001199107.2(TBC1D24):c.1141dup (p.Arg381fs)	TBC1D24	Pathogenic	criteria provided, single submitter
1453407	NM_001199107.2(TBC1D24):c.636G>A (p.Trp212Ter)	TBC1D24	Pathogenic	criteria provided, single submitter
1456664	NM_001199107.2(TBC1D24):c.752del (p.Phe251fs)	TBC1D24	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 113 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ARX	Strong	X-linked	developmental and epileptic encephalopathy, 1	16

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ARX	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
ARX	Orphanet:2508	Corpus callosum agenesis-abnormal genitalia syndrome
ARX	Orphanet:3175	X-linked spasticity-intellectual disability-epilepsy syndrome
ARX	Orphanet:364063	Infantile epileptic-dyskinetic encephalopathy
ARX	Orphanet:452	X-linked lissencephaly with abnormal genitalia
ARX	Orphanet:697160	Infantile epileptic spasms syndrome
ARX	Orphanet:777	X-linked non-syndromic intellectual disability
ARX	Orphanet:94083	Partington 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
SCN1B	Orphanet:130	Brugada syndrome
SCN1B	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
SCN1B	Orphanet:33069	Dravet syndrome
SCN1B	Orphanet:334	Hereditary atrial fibrillation
SCN1B	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN1B	Orphanet:871	Hereditary progressive cardiac conduction defect
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
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
ST3GAL3	Orphanet:697734	ST3GAL3-CDG
SLC25A12	Orphanet:353217	Epileptic encephalopathy with global cerebral demyelination
SLC2A1	Orphanet:168577	Hereditary cryohydrocytosis with reduced stomatin
SLC2A1	Orphanet:1942	Epilepsy with myoclonic-atonic seizures
SLC2A1	Orphanet:2131	Alternating hemiplegia of childhood
SLC2A1	Orphanet:53583	Paroxysmal dystonic choreathetosis with episodic ataxia and spasticity
SLC2A1	Orphanet:71277	Classic glucose transporter type 1 deficiency syndrome
SLC2A1	Orphanet:86911	Epilepsy with myoclonic absences
SLC2A1	Orphanet:98811	Paroxysmal exertion-induced dyskinesia
SLC35A2	Orphanet:268973	Isolated focal cortical dysplasia type Ia
SLC35A2	Orphanet:356961	SLC35A2-CDG
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

Cohort genes → proteins

44 cohort genes, 43 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	44

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ARX	HGNC:18060	ENSG00000004848	Q96QS3	Homeobox protein ARX	gencc,clinvar
SCN1A	HGNC:10585	ENSG00000144285	P35498	Sodium channel protein type 1 subunit alpha	clinvar
SCN1B	HGNC:10586	ENSG00000105711	Q07699	Sodium channel regulatory subunit beta-1	clinvar
SCN2A	HGNC:10588	ENSG00000136531	Q99250	Sodium channel protein type 2 subunit alpha	clinvar
SCN3A	HGNC:10590	ENSG00000153253	Q9NY46	Sodium channel protein type 3 subunit alpha	clinvar
SCN8A	HGNC:10596	ENSG00000196876	Q9UQD0	Sodium channel protein type 8 subunit alpha	clinvar
ST3GAL3	HGNC:10866	ENSG00000126091	Q11203	CMP-N-acetylneuraminate-beta-1,4-galactoside alpha-2,3-sialyltransferase	clinvar
SLC25A12	HGNC:10982	ENSG00000115840	O75746	Electrogenic aspartate/glutamate antiporter SLC25A12, mitochondrial	clinvar
SLC2A1	HGNC:11005	ENSG00000117394	P11166	Solute carrier family 2, facilitated glucose transporter member 1	clinvar
SLC35A2	HGNC:11022	ENSG00000102100	P78381	UDP-galactose translocator	clinvar
CDKL5	HGNC:11411	ENSG00000008086	O76039	Cyclin-dependent kinase-like 5	clinvar
SYNJ1	HGNC:11503	ENSG00000159082	O43426	Synaptojanin-1	clinvar
WWOX	HGNC:12799	ENSG00000186153	Q9NZC7	WW domain-containing oxidoreductase	clinvar
NAPSB	HGNC:13396	ENSG00000131401		napsin B aspartic peptidase (pseudogene)	clinvar
CACNA1A	HGNC:1388	ENSG00000141837	O00555	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	clinvar
PCDH19	HGNC:14270	ENSG00000165194	Q8TAB3	Protocadherin-19	clinvar
ARHGEF9	HGNC:14561	ENSG00000131089	O43307	Rho guanine nucleotide exchange factor 9	clinvar
DYNLRB2	HGNC:15467	ENSG00000168589	Q8TF09	Dynein light chain roadblock-type 2	clinvar
NAPB	HGNC:15751	ENSG00000125814	Q9H115	Beta-soluble NSF attachment protein	clinvar
CCNF	HGNC:1591	ENSG00000162063	P41002	Cyclin-F	clinvar
PLCB1	HGNC:15917	ENSG00000182621	Q9NQ66	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1	clinvar
CHD2	HGNC:1917	ENSG00000173575	O14647	ATP-dependent chromatin remodeler CHD2	clinvar
PACS2	HGNC:23794	ENSG00000179364	Q86VP3	Phosphofurin acidic cluster sorting protein 2	clinvar
CSNK1E	HGNC:2453	ENSG00000213923	P49674	Casein kinase I isoform epsilon	clinvar
MLST8	HGNC:24825	ENSG00000167965	Q9BVC4	Target of rapamycin complex subunit LST8	clinvar
FLYWCH1	HGNC:25404	ENSG00000059122	Q4VC44	FLYWCH-type zinc finger-containing protein 1	clinvar
UFSP2	HGNC:25640	ENSG00000109775	Q9NUQ7	Ufm1-specific protease 2	clinvar
EME2	HGNC:27289	ENSG00000197774	A4GXA9	Structure-specific endonuclease subunit EME2	clinvar
SZT2	HGNC:29040	ENSG00000198198	Q5T011	KICSTOR complex protein SZT2	clinvar
TBC1D24	HGNC:29203	ENSG00000162065	Q9ULP9	TBC1 domain family member 24	clinvar
DNM1	HGNC:2972	ENSG00000106976	Q05193	Dynamin-1	clinvar
ALG13	HGNC:30881	ENSG00000101901	Q9NP73	UDP-N-acetylglucosamine transferase subunit ALG13	clinvar
GABRB3	HGNC:4083	ENSG00000166206	P28472	Gamma-aminobutyric acid receptor subunit beta-3	clinvar
GNAO1	HGNC:4389	ENSG00000087258	P09471	Guanine nucleotide-binding protein G(o) subunit alpha	clinvar
GRIN1	HGNC:4584	ENSG00000176884	Q05586	Glutamate receptor ionotropic, NMDA 1	clinvar
HNRNPU	HGNC:5048	ENSG00000153187	Q00839	Heterogeneous nuclear ribonucleoprotein U	clinvar
KCNA2	HGNC:6220	ENSG00000177301	P16389	Potassium voltage-gated channel subfamily A member 2	clinvar
KCNQ2	HGNC:6296	ENSG00000075043	O43526	Potassium voltage-gated channel subfamily KQT member 2	clinvar
MAF	HGNC:6776	ENSG00000178573	O75444	Transcription factor Maf	clinvar
MDH2	HGNC:6971	ENSG00000146701	P40926	Malate dehydrogenase, mitochondrial	clinvar
ATP1A2	HGNC:800	ENSG00000018625	P50993	Sodium/potassium-transporting ATPase subunit alpha-2	clinvar
NRXN2	HGNC:8009	ENSG00000110076	P58401	Neurexin-2-beta	clinvar
ALDH7A1	HGNC:877	ENSG00000164904	P49419	Alpha-aminoadipic semialdehyde dehydrogenase	clinvar
REPS2	HGNC:9963	ENSG00000169891	Q8NFH8	RalBP1-associated Eps domain-containing protein 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ARX	Homeobox protein ARX	Transcription factor.
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.
SCN1B	Sodium channel regulatory subunit beta-1	Regulatory subunit of multiple voltage-gated sodium (Nav) channels directly mediating the depolarization of 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.
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…
ST3GAL3	CMP-N-acetylneuraminate-beta-1,4-galactoside alpha-2,3-sialyltransferase	Catalyzes the formation of the NeuAc-alpha-2,3-Gal-beta-1,4-GlcNAc-, NeuAc-alpha-2,3-Gal-beta-1,3-GlcNAc- and NeuAc-alpha-2,3-Gal-beta-1,3-GalNAc- sequences found in terminal carbohydrate groups of glycoproteins and glycolipids.
SLC25A12	Electrogenic aspartate/glutamate antiporter SLC25A12, mitochondrial	Mitochondrial electrogenic aspartate/glutamate antiporter that favors efflux of aspartate and entry of glutamate and proton within the mitochondria as part of the malate-aspartate shuttle.
SLC2A1	Solute carrier family 2, facilitated glucose transporter member 1	Facilitative glucose transporter, which is responsible for constitutive or basal glucose uptake.
SLC35A2	UDP-galactose translocator	Transports uridine diphosphate galactose (UDP-galactose) from the cytosol into the Golgi apparatus, functioning as an antiporter that exchanges UDP-galactose for UMP.
CDKL5	Cyclin-dependent kinase-like 5	Mediates phosphorylation of MECP2.
SYNJ1	Synaptojanin-1	Phosphatase that acts on various phosphoinositides, including phosphatidylinositol 4-phosphate, phosphatidylinositol (4,5)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate.
WWOX	WW domain-containing oxidoreductase	Putative oxidoreductase.
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…
PCDH19	Protocadherin-19	Calcium-dependent cell-adhesion protein.
ARHGEF9	Rho guanine nucleotide exchange factor 9	Acts as a guanine nucleotide exchange factor (GEF) for CDC42.
DYNLRB2	Dynein light chain roadblock-type 2	Acts as one of several non-catalytic accessory components of the cytoplasmic dynein 1 complex that are thought to be involved in linking dynein to cargos and to adapter proteins that regulate dynein function.
NAPB	Beta-soluble NSF attachment protein	Required for vesicular transport between the endoplasmic reticulum and the Golgi apparatus.
CCNF	Cyclin-F	Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.
PLCB1	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1	Catalyzes the hydrolysis of 1-phosphatidylinositol 4,5-bisphosphate into diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) and mediates intracellular signaling downstream of G protein-coupled receptors.
CHD2	ATP-dependent chromatin remodeler CHD2	ATP-dependent chromatin-remodeling factor that specifically binds to the promoter of target genes, leading to chromatin remodeling, possibly by promoting deposition of histone H3.3.
PACS2	Phosphofurin acidic cluster sorting protein 2	Multifunctional sorting protein that controls the endoplasmic reticulum (ER)-mitochondria communication, including the apposition of mitochondria with the ER and ER homeostasis.
CSNK1E	Casein kinase I isoform epsilon	Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates.
MLST8	Target of rapamycin complex subunit LST8	Subunit of both mTORC1 and mTORC2, which regulates cell growth and survival in response to nutrient and hormonal signals. mTORC1 is activated in response to growth factors or amino acids.
FLYWCH1	FLYWCH-type zinc finger-containing protein 1	Transcription cofactor.
UFSP2	Ufm1-specific protease 2	Thiol-dependent isopeptidase that specifically cleaves UFM1, a ubiquitin-like modifier protein, from conjugated proteins, such as CD274/PD-L1, CYB5R3, DDRGK1, MRE11, RPL26/uL24, TRIP4 and RPL26/uL24.
EME2	Structure-specific endonuclease subunit EME2	Non-catalytic subunit of the structure-specific, heterodimeric DNA endonuclease MUS81-EME2 which is involved in the maintenance of genome stability.
SZT2	KICSTOR complex protein SZT2	As part of the KICSTOR complex functions in the amino acid-sensing branch of the TORC1 signaling pathway.
TBC1D24	TBC1 domain family member 24	May act as a GTPase-activating protein for Rab family protein(s).
DNM1	Dynamin-1	Catalyzes the hydrolysis of GTP and utilizes this energy to mediate vesicle scission and participates in many forms of endocytosis, such as clathrin-mediated endocytosis or synaptic vesicle endocytosis as well as rapid endocytosis (RE).
ALG13	UDP-N-acetylglucosamine transferase subunit ALG13	Catalytic subunit of the UDP-N-acetylglucosamine transferase complex that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation.
GABRB3	Gamma-aminobutyric acid receptor subunit beta-3	Beta subunit of the heteropentameric ligand-gated chloride channel gated by gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain.
GNAO1	Guanine nucleotide-binding protein G(o) subunit alpha	Guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs) in numerous signaling cascades.
GRIN1	Glutamate receptor ionotropic, NMDA 1	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+).
HNRNPU	Heterogeneous nuclear ribonucleoprotein U	DNA- and RNA-binding protein involved in several cellular processes such as nuclear chromatin organization, telomere-length regulation, transcription, mRNA alternative splicing and stability, Xist-mediated transcriptional silencing and mit…
KCNA2	Potassium voltage-gated channel subfamily A member 2	Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain and the central nervous system, but also in the cardiovascular system.
KCNQ2	Potassium voltage-gated channel subfamily KQT member 2	Pore-forming subunit of the voltage-gated potassium (Kv) M-channel which is responsible for the M-current, a key controller of neuronal excitability.
MAF	Transcription factor Maf	Acts as a transcriptional activator or repressor.
ATP1A2	Sodium/potassium-transporting ATPase subunit alpha-2	This is the catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane.
NRXN2	Neurexin-2-beta	Neuronal cell surface protein that may be involved in cell recognition and cell adhesion.
ALDH7A1	Alpha-aminoadipic semialdehyde dehydrogenase	Aldehyde dehydrogenase enzyme that mediates important protective effects.
REPS2	RalBP1-associated Eps domain-containing protein 2	Involved in ligand-dependent receptor mediated endocytosis of the EGF and insulin receptors as part of the Ral signaling pathway.

Protein-family classification

Druggable: 16 · Difficult: 8 · Unknown: 20 · Druggable fraction: 0.36

Family distribution

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

Family	Genes	Fold	FDR
Ion channel	7	17.7×	1e-06
Transporter	2	3.5×	0.438
Scaffold/PPI	4	1.6×	0.664
Kinase	2	1.3×	0.809
Enzyme (other)	4	1.1×	0.809
Transcription factor	4	0.8×	0.910
Antibody/Immunoglobulin	1	0.7×	0.910
Other/Unknown	20	0.8×	0.937

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ARX	Transcription factor	no		HD, OAR_dom, Homeodomain-like_sf
SCN1A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a1su
SCN1B	Antibody/Immunoglobulin	yes		Ig_V-set, Ig-like_fold, Na_channel_b1/b3
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
SCN8A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
ST3GAL3	Enzyme (other)	yes	2.4.99.2	Glyco_trans_29, Sialyl_trans, GT29-like_sf
SLC25A12	Transporter	yes		EF_hand_dom, MCP, EF-hand-dom_pair
SLC2A1	Transporter	yes		Glu_transpt_1, Sugar/inositol_transpt, MFS_sugar_transport-like
SLC35A2	Other/Unknown	no		Nuc_sug_transpt, EmrE-like
CDKL5	Kinase	yes	2.7.11.22	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
SYNJ1	Other/Unknown	no		IPPc, RRM_dom, SAC_dom
WWOX	Scaffold/PPI	no		WW_dom, SDR_fam, WW_dom_sf
NAPSB	Other/Unknown	no
CACNA1A	Ion channel	yes		VDCCAlpha1, CACNA1A, Ion_trans_dom
PCDH19	Other/Unknown	no		Cadherin-like_dom, Cadherin_N, Cadherin-like_sf
ARHGEF9	Scaffold/PPI	no		DH_dom, SH3_domain, PH_domain
DYNLRB2	Other/Unknown	no		Roadblock/LAMTOR2_dom, DYNLRB1/2
NAPB	Other/Unknown	no		NSF_attach, TPR-like_helical_dom_sf
CCNF	Other/Unknown	no		F-box_dom, Cyclin_C-dom, Cyclin_N
PLCB1	Enzyme (other)	yes	3.1.4.11	C2_dom, PLipase_C_PInositol-sp_X_dom, PI-PLC_fam
CHD2	Other/Unknown	no		SNF2_N, Chromo/chromo_shadow_dom, Helicase_C-like
PACS2	Other/Unknown	no		PACS1/2_C, PACS1/2_N
CSNK1E	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
MLST8	Scaffold/PPI	no		WD40_rpt, Quinoprotein_ADH-like_sf, WD40/YVTN_repeat-like_dom_sf
FLYWCH1	Transcription factor	no		Znf_FLYWCH, FLYWCH_N, FWCH1/FWCH2
UFSP2	Other/Unknown	no		UFSP1/2_DUB_cat, UFSP2-like_2nd
EME2	Other/Unknown	no		ERCC4_domain, Mms4/EME1/EME2, EME1/EME2_C
SZT2	Other/Unknown	no		SZT2
TBC1D24	Other/Unknown	no		Rab-GAP-TBC_dom, TLDc_dom, Rab-GAP_TBC_sf
DNM1	Scaffold/PPI	no	3.6.5.5	Dynamin_stalk, Dynamin_GTPase, PH_domain
ALG13	Other/Unknown	no		Tudor, OTU_dom, Glyco_trans_28_C
GABRB3	Other/Unknown	no		GABAAb_rcpt, GABAA/Glycine_rcpt, Neurotrans-gated_channel_TM
GNAO1	Other/Unknown	no		Gprotein_alpha_su, Gprotein_alpha_I, GproteinA_insert
GRIN1	Other/Unknown	no		Iontro_rcpt_C, Iono_Glu_rcpt_met, ANF_lig-bd_rcpt
HNRNPU	Other/Unknown	no		B30.2/SPRY, SAP_dom, SPRY_dom
KCNA2	Ion channel	yes		BTB/POZ_dom, T1-type_BTB, K_chnl_volt-dep_Kv
KCNQ2	Ion channel	yes		K_chnl_volt-dep_KCNQ, K_chnl_volt-dep_KCNQ2, Ion_trans_dom
MAF	Transcription factor	no		bZIP_Maf, bZIP, TF_DNA-bd_sf
MDH2	Enzyme (other)	yes	1.1.1.37	Lactate/malate_DH_N, Malate_DH_AS, L-lactate/malate_DH
ATP1A2	Transcription factor	no		P_typ_ATPase, ATPase_P-typ_cation-transptr_N, P-type_ATPase_IIC
NRXN2	Other/Unknown	no		Laminin_G, Neurexin-like, ConA-like_dom_sf
ALDH7A1	Enzyme (other)	yes	1.2.1.3	Aldehyde_DH_dom, Ald_DH/histidinol_DH, Ald_DH_N
REPS2	Other/Unknown	no		EH_dom, EF_hand_dom, EF-hand-dom_pair

Expression context

Cohort genes with no expression data: 0.

43 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)	44
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	10
right hemisphere of cerebellum	10
middle temporal gyrus	9
cerebellar hemisphere	8
cortical plate	6
cerebellar cortex	6
left ovary	3
lateral nuclear group of thalamus	3
endothelial cell	3
sural nerve	3
calcaneal tendon	3
primary visual cortex	2
hindlimb stylopod muscle	2
triceps brachii	2
bronchial epithelial cell	2
parotid gland	2
granulocyte	2
entorhinal cortex	2
right uterine tube	2
type B pancreatic cell	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ARX	162	broad	marker	left ovary, ovary, right ovary
SCN1A	154	tissue_specific	marker	Brodmann (1909) area 23, lateral nuclear group of thalamus, primary visual cortex
SCN1B	133	ubiquitous	marker	primary visual cortex, right hemisphere of cerebellum, cerebellum
SCN2A	187	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, cerebellar vermis
SCN3A	221	broad	marker	endothelial cell, cortical plate, middle temporal gyrus
SCN8A	194	ubiquitous	marker	Brodmann (1909) area 23, middle temporal gyrus, postcentral gyrus
ST3GAL3	178	ubiquitous	marker	hindlimb stylopod muscle, gastrocnemius, muscle of leg
SLC25A12	295	ubiquitous	marker	biceps brachii, skeletal muscle tissue of biceps brachii, triceps brachii
SLC2A1	250	ubiquitous	marker	tibial nerve, sural nerve, skin of abdomen
SLC35A2	277	ubiquitous	marker	secondary oocyte, bronchial epithelial cell, epithelium of bronchus
CDKL5	257	ubiquitous	marker	frontal pole, Brodmann (1909) area 23, cortical plate
SYNJ1	278	ubiquitous	yes	Brodmann (1909) area 23, lateral nuclear group of thalamus, pons
WWOX	286	ubiquitous	marker	parotid gland, cervix squamous epithelium, cranial nerve II
NAPSB	192	broad	marker	granulocyte, spleen, vermiform appendix
CACNA1A	237	broad	marker	cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex
PCDH19	175	broad	marker	cortical plate, entorhinal cortex, middle temporal gyrus
ARHGEF9	264	ubiquitous	marker	Brodmann (1909) area 46, prefrontal cortex, CA1 field of hippocampus
DYNLRB2	182	broad	marker	bronchial epithelial cell, right uterine tube, bronchus
NAPB	245	ubiquitous	marker	middle temporal gyrus, Brodmann (1909) area 23, endothelial cell
CCNF	213	ubiquitous	marker	type B pancreatic cell, olfactory bulb, hair follicle
PLCB1	278	ubiquitous	marker	endothelial cell, Brodmann (1909) area 23, superior frontal gyrus
CHD2	268	ubiquitous	marker	calcaneal tendon, sural nerve, colonic epithelium
PACS2	281	ubiquitous	marker	C1 segment of cervical spinal cord, spinal cord, right hemisphere of cerebellum
CSNK1E	275	ubiquitous	marker	cortical plate, ganglionic eminence, left ovary
MLST8	263	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
FLYWCH1	249	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
UFSP2	290	ubiquitous	marker	calcaneal tendon, hindlimb stylopod muscle, triceps brachii
EME2	231	ubiquitous	marker	oviduct epithelium, right hemisphere of cerebellum, cerebellar hemisphere
SZT2	238	ubiquitous	marker	colonic epithelium, sural nerve, granulocyte
TBC1D24	227	ubiquitous	marker	parotid gland, Brodmann (1909) area 23, middle temporal gyrus

Protein interactions among cohort

Intra-cohort edges: 39.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CCNF	6,626
WWOX	5,892
MDH2	5,749
SLC2A1	5,711
HNRNPU	5,328
ALDH7A1	4,544
MAF	4,111
DNM1	3,614
GNAO1	3,437
KCNQ2	3,388

Intra-cohort edges

A	B	Sources
ALG13	CDKL5	string_interaction
ALG13	GABRB3	string_interaction
ARHGEF9	ARX	string_interaction
ARHGEF9	CDKL5	string_interaction
ARHGEF9	PCDH19	string_interaction
ARHGEF9	PLCB1	string_interaction
ARX	CDKL5	string_interaction
ARX	PCDH19	string_interaction
ARX	PLCB1	string_interaction
ARX	SCN1A	string_interaction
ATP1A2	SCN1A	string_interaction
ATP1A2	SLC2A1	string_interaction
CDKL5	GABRB3	string_interaction
CDKL5	KCNQ2	string_interaction
CDKL5	PCDH19	string_interaction
CDKL5	SCN1A	string_interaction
CDKL5	SCN2A	string_interaction
DNM1	SYNJ1	string_interaction
GABRB3	SCN1A	string_interaction
KCNA2	SCN3A	string_interaction
KCNA2	SCN8A	string_interaction
KCNQ2	PCDH19	string_interaction
KCNQ2	SCN1A	string_interaction
KCNQ2	SCN2A	string_interaction
KCNQ2	SCN3A	string_interaction
KCNQ2	SCN8A	string_interaction
PCDH19	PLCB1	string_interaction
PCDH19	SCN1A	string_interaction
PCDH19	SCN1B	string_interaction
PCDH19	SCN2A	string_interaction
PCDH19	TBC1D24	string_interaction
SCN1A	SCN1B	biogrid_interaction, string_interaction
SCN1A	SCN2A	biogrid_interaction, string_interaction
SCN1A	TBC1D24	string_interaction
SCN1B	SCN2A	string_interaction
SCN1B	SCN3A	string_interaction
SCN1B	SCN8A	string_interaction
SCN2A	SCN3A	intact
SCN2A	TBC1D24	string_interaction

Structural data

PDB: 29 · AlphaFold-only: 14 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GABRB3	P28472	95
GNAO1	P09471	86
GRIN1	Q05586	85
MLST8	Q9BVC4	45
SCN1B	Q07699	39
KCNQ2	O43526	39
DNM1	Q05193	22
ALDH7A1	P49419	20
SZT2	Q5T011	9
SCN8A	Q9UQD0	7
MDH2	P40926	7
SCN2A	Q99250	5
SLC2A1	P11166	5
SYNJ1	O43426	5
CACNA1A	O00555	4
CDKL5	O76039	3
SCN3A	Q9NY46	2
SLC25A12	O75746	2
CSNK1E	P49674	2
SCN1A	P35498	1
WWOX	Q9NZC7	1
PCDH19	Q8TAB3	1
ARHGEF9	O43307	1
DYNLRB2	Q8TF09	1
CCNF	P41002	1
FLYWCH1	Q4VC44	1
EME2	A4GXA9	1
NRXN2	P58401	1
REPS2	Q8NFH8	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
UFSP2	Q9NUQ7	91.21
ST3GAL3	Q11203	90.87
NAPB	Q9H115	89.55
ATP1A2	P50993	88.25
PLCB1	Q9NQ66	84.55
TBC1D24	Q9ULP9	84.46
SLC35A2	P78381	80.59
KCNA2	P16389	78.01
PACS2	Q86VP3	67.10
HNRNPU	Q00839	65.89
MAF	O75444	62.21
CHD2	O14647	60.81
ARX	Q96QS3	56.51
ALG13	Q9NP73	54.42

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 231. Enrichment computed across 44 evidence-associated genes (38 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 38 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	6	58.2×	1e-07	SCN1A, SCN1B, SCN2A, SCN3A, SCN8A, KCNQ2
Phase 0 - rapid depolarisation	5	45.5×	8e-06	SCN1A, SCN1B, SCN2A, SCN3A, SCN8A
L1CAM interactions	6	19.0×	5e-05	SCN1A, SCN1B, SCN2A, SCN3A, SCN8A, KCNQ2
Cardiac conduction	6	17.2×	7e-05	SCN1A, SCN1B, SCN2A, SCN3A, SCN8A, ATP1A2
Muscle contraction	6	12.2×	4e-04	SCN1A, SCN1B, SCN2A, SCN3A, SCN8A, ATP1A2
Sensory perception of taste	3	26.5×	0.006	SCN1B, SCN2A, SCN3A
Axon guidance	6	7.1×	0.006	SCN1A, SCN1B, SCN2A, SCN3A, SCN8A, KCNQ2
Nervous system development	6	6.8×	0.006	SCN1A, SCN1B, SCN2A, SCN3A, SCN8A, KCNQ2
Sensory perception of sweet, bitter, and umami (glutamate) taste	3	22.0×	0.009	SCN1B, SCN2A, SCN3A
Malate-aspartate shuttle	2	66.8×	0.009	SLC25A12, MDH2
Defective SLC2A1 causes GLUT1 deficiency syndrome 1 (GLUT1DS1)	1	300.5×	0.064	SLC2A1
Defective SLC35A2 causes congenital disorder of glycosylation 2M (CDG2M)	1	300.5×	0.064	SLC35A2
Synthesis of IP3 and IP4 in the cytosol	2	22.3×	0.064	SYNJ1, PLCB1
Defective ALG14 causes ALG14-CMS	1	150.3×	0.102	ALG13
GABA receptor activation	2	16.7×	0.102	ARHGEF9, GABRB3
Sensory Perception	3	7.5×	0.105	SCN1B, SCN2A, SCN3A
Lactose synthesis	1	100.2×	0.123	SLC2A1
Voltage gated Potassium channels	2	12.8×	0.123	KCNA2, KCNQ2
Clathrin-mediated endocytosis	3	6.7×	0.123	SYNJ1, DNM1, REPS2
Neuronal System	4	4.7×	0.123	CACNA1A, ARHGEF9, KCNA2, KCNQ2
Regulation of insulin secretion	2	11.6×	0.142	SLC2A1, CACNA1A
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	2	10.9×	0.150	ST3GAL3, ALG13
Amino acids regulate mTORC1	2	10.5×	0.153	MLST8, SZT2
Neurexins and neuroligins	2	10.4×	0.153	GRIN1, NRXN2
Ca2+ pathway	2	9.4×	0.176	PLCB1, GNAO1
Vitamin C (ascorbate) metabolism	1	37.6×	0.189	SLC2A1
WNT mediated activation of DVL	1	37.6×	0.189	CSNK1E
Defective ST3GAL3 causes MCT12 and EIEE15	1	37.6×	0.189	ST3GAL3
Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion	1	37.6×	0.189	PLCB1
Choline catabolism	1	37.6×	0.189	ALDH7A1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 43 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
sodium ion transmembrane transport	7	33.0×	6e-07	SCN1A, SCN1B, SCN2A, SCN3A, SCN8A, GRIN1, ATP1A2
cardiac muscle cell action potential involved in contraction	5	81.7×	7e-07	SCN1A, SCN1B, SCN2A, SCN3A, SCN8A
sodium ion transport	5	31.6×	7e-05	SCN1A, SCN2A, SCN3A, SCN8A, ATP1A2
membrane depolarization during action potential	3	117.6×	2e-04	SCN1A, SCN1B, SCN3A
neuronal action potential propagation	3	98.0×	3e-04	SCN1A, SCN1B, ATP1A2
neuronal action potential	3	33.6×	0.007	SCN1A, SCN2A, KCNA2
malate-aspartate shuttle	2	87.1×	0.012	SLC25A12, MDH2
action potential	3	25.0×	0.012	SCN8A, KCNA2, KCNQ2
L-ascorbic acid metabolic process	2	71.3×	0.014	SLC2A1, ATP1A2
locomotion	2	71.3×	0.014	SCN1B, ATP1A2
membrane depolarization during cardiac muscle cell action potential	2	65.3×	0.016	SCN1B, ATP1A2
learning	3	19.6×	0.017	SYNJ1, PLCB1, GABRB3
propylene metabolic process	1	391.9×	0.031	GRIN1
reproductive behavior	1	391.9×	0.031	GABRB3
L-lysine catabolic process	1	391.9×	0.031	ALDH7A1
corticospinal neuron axon guidance	1	391.9×	0.031	SCN1B
olfactory cortex development	1	391.9×	0.031	ATP1A2
circadian sleep/wake cycle, REM sleep	1	391.9×	0.031	GABRB3
clathrin coat assembly involved in endocytosis	1	391.9×	0.031	DNM1
regulation of superoxide dismutase activity	1	391.9×	0.031	SZT2
protein localization to spindle microtubule	1	391.9×	0.031	HNRNPU
positive regulation of endosome organization	1	391.9×	0.031	SYNJ1
response to glycine	1	391.9×	0.031	GRIN1
cellular response to glyceraldehyde	1	391.9×	0.031	PLCB1
negative regulation of endosome to plasma membrane protein transport	1	391.9×	0.031	ALDH7A1
RNA localization to chromatin	1	391.9×	0.031	HNRNPU
negative regulation of monocyte extravasation	1	391.9×	0.031	PLCB1
phosphatidylinositol metabolic process	2	41.2×	0.031	SYNJ1, PLCB1
positive regulation of dendrite morphogenesis	2	41.2×	0.031	CDKL5, TBC1D24
postsynaptic modulation of chemical synaptic transmission	2	31.4×	0.031	PLCB1, GNAO1

Therapeutics

Drug target analysis

Approved (phase 4): 16 · Phase ≥3: 17 · Phased (≥1): 18 · Undrugged: 26

Druggability breadth: 24 of 44 evidence-associated genes (55%) 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
SCN8A	IMIPRAMINE
SLC2A1	EMETINE
CDKL5	FEDRATINIB
SYNJ1	PYRVINIUM
CACNA1A	NIMODIPINE
CSNK1E	AFATINIB
MLST8	EVEROLIMUS
DNM1	CETRIMIDE
GABRB3	LINDANE
GRIN1	DEXTROMETHORPHAN
KCNQ2	FLUPIRTINE
MDH2	LEVOTHYROXINE
ATP1A2	OMEPRAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN2A	99	4
SCN1A	94	4
SCN3A	93	4
GRIN1	39	4
CSNK1E	37	4
GABRB3	32	4
SCN8A	25	4
CDKL5	14	4
MLST8	13	4
SLC2A1	7	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, 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	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

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 7.

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

Symbol	Assays	Type breakdown
GABRB3	887	Binding:722, Functional:156, ADMET:6, Toxicity:3
GRIN1	481	Binding:435, Functional:40, ADMET:5, Toxicity:1
CSNK1E	420	Binding:416, ADMET:2, Functional:2
MLST8	275	Binding:275
SCN2A	203	Binding:172, Functional:20, ADMET:10, Toxicity:1
SCN8A	173	Binding:148, Functional:16, ADMET:7, Toxicity:2
SLC2A1	158	Binding:130, ADMET:24, Functional:4
SCN1A	149	Binding:115, Functional:18, ADMET:14, Toxicity:2
KCNQ2	145	Binding:136, Functional:7, ADMET:1, Toxicity:1
SCN3A	102	Binding:79, Functional:18, ADMET:4, Toxicity:1
CDKL5	74	Binding:74
ATP1A2	49	Binding:49
KCNA2	36	Binding:31, Functional:3, ADMET:1, Toxicity:1
MDH2	28	Binding:28
CACNA1A	19	Binding:18, Functional:1
SCN1B	15	Binding:7, ADMET:6, Toxicity:2
GNAO1	12	Functional:10, Binding:2
PLCB1	11	Binding:9, Functional:2
DNM1	11	Binding:11
HNRNPU	9	Binding:9
ST3GAL3	2	Binding:2
SYNJ1	2	Binding:2
SLC35A2	1	ADMET:1
ALDH7A1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ST3GAL3	2.4.99.2, 2.4.99.6	beta-D-galactosyl-(1->3)-N-acetyl-beta-D-galactosaminide alpha-2,3-sialyltransferase, N-acetyllactosaminide alpha-2,3-sialyltransferase
CDKL5	2.7.11.22	cyclin-dependent kinase
PLCB1	3.1.4.11	phosphoinositide phospholipase C
CSNK1E	2.7.11.1	non-specific serine/threonine protein kinase
DNM1	3.6.5.5	dynamin GTPase
MDH2	1.1.1.37	(S)-malate dehydrogenase (NAD+, oxaloacetate-forming)
ALDH7A1	1.2.1.3, 1.2.1.31	aldehyde dehydrogenase (NAD+), L-aminoadipate-semialdehyde dehydrogenase

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
SCN8A	173
SLC2A1	158
CSNK1E	420
MLST8	275
GABRB3	887
GRIN1	481
KCNQ2	145

Pharmacogenomics

Cohort genes with a PharmGKB record: 43; 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, 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	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

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	16	SCN1A, SCN2A, SCN3A, SCN8A, SLC2A1, CDKL5, SYNJ1, CACNA1A, CSNK1E, MLST8 (+6 more)
B	Phased (≥1) drug, not yet approved	2	SCN1B, KCNA2
C	Druggable family + PDB, no drug	2	SLC25A12, ALDH7A1
D	Druggable family + AlphaFold only, no drug	2	ST3GAL3, PLCB1
E	Difficult family or no structure, no drug	22	ARX, SLC35A2, WWOX, NAPSB, PCDH19, ARHGEF9, DYNLRB2, NAPB, CCNF, CHD2 (+12 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ARX	0	CDKL5
PCDH19	0	SCN1A, CDKL5, KCNQ2
ST3GAL3	2	—
SLC25A12	0	—
SLC35A2	1	—
WWOX	0	—
NAPSB	0	—
ARHGEF9	0	—
DYNLRB2	0	—
NAPB	0	—
CCNF	0	—
PLCB1	11	—
CHD2	0	—
PACS2	0	—
FLYWCH1	0	—
UFSP2	0	—
EME2	0	—
SZT2	0	—
TBC1D24	0	—
ALG13	0	—
GNAO1	12	—
HNRNPU	9	—
MAF	0	—
NRXN2	0	—
ALDH7A1	1	—
REPS2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.