Undetermined early-onset epileptic encephalopathy

Summary

Undetermined early-onset epileptic encephalopathy (MONDO:0018614) is a disease (an umbrella term covering 16 Mondo subtypes) caused by variants in AARS1, CACNA1A, and YWHAG, with 48 cohort genes. The dominant Reactome pathway is Phase 0 - rapid depolarisation (5 cohort genes).

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal genes: AARS1 (GenCC Definitive), CACNA1A (GenCC Definitive), YWHAG (GenCC Strong)
• Umbrella term: 16 Mondo subtypes
• Cohort genes: 48
• ClinVar variants: 13
• Phenotypes (HPO): 48

Clinical features

Signs & symptoms

Clinical features (HPO)

48 HPO clinical features (Orphanet curated; top 48 by frequency):

HPO ID	Term	Frequency
HP:0001298	Encephalopathy	Very frequent (80-99%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001265	Hyporeflexia	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0002376	Developmental regression	Frequent (30-79%)
HP:0010844	EEG with multifocal slow activity	Frequent (30-79%)
HP:0011443	Abnormality of coordination	Frequent (30-79%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000348	High forehead	Occasional (5-29%)
HP:0000494	Downslanted palpebral fissures	Occasional (5-29%)
HP:0000508	Ptosis	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000668	Hypodontia	Occasional (5-29%)
HP:0000708	Atypical behavior	Occasional (5-29%)
HP:0000717	Autism	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001257	Spasticity	Occasional (5-29%)
HP:0001268	Mental deterioration	Occasional (5-29%)
HP:0001273	Abnormal corpus callosum morphology	Occasional (5-29%)
HP:0001288	Gait disturbance	Occasional (5-29%)
HP:0001315	Reduced tendon reflexes	Occasional (5-29%)
HP:0001336	Myoclonus	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0001558	Decreased fetal movement	Occasional (5-29%)
HP:0002020	Gastroesophageal reflux	Occasional (5-29%)
HP:0002059	Cerebral atrophy	Occasional (5-29%)
HP:0002063	Rigidity	Occasional (5-29%)
HP:0002317	Unsteady gait	Occasional (5-29%)
HP:0002421	Poor head control	Occasional (5-29%)
HP:0002521	Hypsarrhythmia	Occasional (5-29%)
HP:0004305	Involuntary movements	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0007018	Attention deficit hyperactivity disorder	Occasional (5-29%)
HP:0011968	Feeding difficulties	Occasional (5-29%)
HP:0012444	Brain atrophy	Occasional (5-29%)
HP:0012447	Abnormal myelination	Occasional (5-29%)
HP:0100660	Dyskinesia	Occasional (5-29%)
HP:0100710	Impulsivity	Occasional (5-29%)
HP:0000504	Abnormality of vision	Very rare (<1-4%)
HP:0000546	Retinal degeneration	Very rare (<1-4%)
HP:0000648	Optic atrophy	Very rare (<1-4%)
HP:0002133	Status epilepticus	Very rare (<1-4%)
HP:0002509	Limb hypertonia	Very rare (<1-4%)
HP:0012547	Abnormal involuntary eye movements	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	undetermined early-onset epileptic encephalopathy
Mondo ID	MONDO:0018614
Orphanet	442835
UMLS	C5680057
MedGen	1826068
GARD	0015028
Is cancer (heuristic)	no

Also known as: non-specific early-onset epileptic encephalopathy · undetermined early-onset epileptic encephalopathy · undetermined EOEE

Data availability: 13 ClinVar variants · 44 GenCC gene-disease records · 46 cell lines.

Disease family

An umbrella term covering 16 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › inborn disorder of amino acid transport › undetermined early-onset epileptic encephalopathy

Related subtypes (18): blue diaper syndrome, ocular cystinosis, juvenile nephropathic cystinosis, cystinuria, hyperdibasic aminoaciduria type 1, lysinuric protein intolerance, dicarboxylic aminoaciduria, Hartnup disease, histidinuria due to a renal tubular defect, iminoglycinuria, oculocerebrorenal syndrome, hypotonia-cystinuria syndrome, foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome, episodic ataxia type 6, progressive essential tremor-speech impairment-facial dysmorphism-intellectual disability-abnormal behavior syndrome, disorder of neutral amino acid transport, autosomal recessive cerebellar ataxia - pyramidal signs - nystagmus - oculomotor apraxia syndrome, nephropathic infantile cystinosis

Subtypes (16): developmental and epileptic encephalopathy, 13, developmental and epileptic encephalopathy, 21, developmental and epileptic encephalopathy, 24, developmental and epileptic encephalopathy, 25, developmental and epileptic encephalopathy, 26, developmental and epileptic encephalopathy, 28, developmental and epileptic encephalopathy, 29, developmental and epileptic encephalopathy, 31A, developmental and epileptic encephalopathy, 32, developmental and epileptic encephalopathy, 33, developmental and epileptic encephalopathy, 41, developmental and epileptic encephalopathy, 42, developmental and epileptic encephalopathy, 44, developmental and epileptic encephalopathy, 45, developmental and epileptic encephalopathy, 46, developmental and epileptic encephalopathy, 47

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

13 retrieved; paginated sample, class counts are floors:

6 likely pathogenic, 3 pathogenic/likely pathogenic, 2 pathogenic, 1 uncertain significance, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1285235	NM_001111125.3(IQSEC2):c.4264_4265del (p.Gln1422fs)	IQSEC2	Pathogenic	criteria provided, single submitter
2674589	NM_002314.4(LIMK1):c.1532G>C (p.Gly511Ala)	LIMK1	Pathogenic	no assertion criteria provided
2851717	NM_001330260.2(SCN8A):c.4445C>A (p.Thr1482Asn)	SCN8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
140753	NM_177550.5(SLC13A5):c.680C>T (p.Thr227Met)	SLC13A5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
160028	NM_001130438.3(SPTAN1):c.6899ACCAGCTGG[3] (p.2300DQL[3])	SPTAN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1527917	NM_152296.5(ATP1A3):c.235del (p.Trp79fs)	ATP1A3	Likely pathogenic	criteria provided, single submitter
3236475	NM_016390.4(SPOUT1):c.292G>A (p.Gly98Ser)	KYAT1-SPOUT1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
495280	NC_000016.10:g.(?6316970)(6317082_?)del	RBFOX1	Likely pathogenic	criteria provided, single submitter
495281	NC_000016.10:g.(?6654578)(6654675_?)del	RBFOX1	Likely pathogenic	criteria provided, single submitter
495282	NC_000001.10:g.(?206579711)(206634815_?)dup	SRGAP2	Likely pathogenic	criteria provided, single submitter
495283	NC_000001.10:g.(?206516175)(206567055_?)dup	SRGAP2	Likely pathogenic	criteria provided, single submitter
488917	NM_001037.5(SCN1B):c.196G>T (p.Glu66Ter)	SCN1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
424463	NM_001127222.2(CACNA1A):c.6527G>T (p.Gly2176Val)	CACNA1A	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 296 · Orphanet: 94 · 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
AARS1	Definitive	Autosomal recessive	undetermined early-onset epileptic encephalopathy	13
ACTL6B	Definitive	Autosomal recessive	developmental and epileptic encephalopathy, 76	10
ATP6V1A	Definitive	Autosomal dominant	developmental and epileptic encephalopathy 93	11
CACNA1A	Definitive	Autosomal dominant	undetermined early-onset epileptic encephalopathy	23
CYFIP2	Definitive	Autosomal dominant	developmental and epileptic encephalopathy, 65	4
FGF12	Definitive	Autosomal dominant	developmental and epileptic encephalopathy, 47	5
GABRB2	Definitive	Autosomal dominant	developmental and epileptic encephalopathy 92	5
HCN1	Definitive	Autosomal dominant	developmental and epileptic encephalopathy, 24	7
KCNA2	Definitive	Autosomal dominant	developmental and epileptic encephalopathy, 32	4
KCNB1	Definitive	Autosomal dominant	developmental and epileptic encephalopathy, 26	6
SCN3A	Definitive	Autosomal dominant	genetic developmental and epileptic encephalopathy	7
SCN8A	Definitive	Autosomal dominant	developmental and epileptic encephalopathy, 13	13
SLC13A5	Definitive	Autosomal recessive	developmental and epileptic encephalopathy, 25	6
STXBP1	Definitive	Autosomal recessive	developmental and epileptic encephalopathy, 4	12
SZT2	Definitive	Autosomal recessive	developmental and epileptic encephalopathy, 18	6
YWHAG	Definitive	Autosomal dominant	developmental and epileptic encephalopathy, 56	6
AP3B2	Strong	Autosomal recessive	developmental and epileptic encephalopathy, 48	4
CDK19	Strong	Autosomal dominant	developmental and epileptic encephalopathy, 87	4
CELF2	Strong	Autosomal dominant	developmental and epileptic encephalopathy 97	5
DNM1	Strong	Autosomal recessive	developmental and epileptic encephalopathy, 31B	10
EEF1A2	Strong	Autosomal dominant	developmental and epileptic encephalopathy, 33	7
FGF13	Strong	X-linked	developmental and epileptic encephalopathy, 90	6
GABRA2	Strong	Autosomal dominant	developmental and epileptic encephalopathy, 78	5
GABRA5	Strong	Autosomal dominant	developmental and epileptic encephalopathy, 79	4
GABRG2	Strong	Autosomal dominant	developmental and epileptic encephalopathy, 74	11
GRIN2D	Strong	Autosomal dominant	developmental and epileptic encephalopathy, 46	5
NECAP1	Strong	Autosomal recessive	developmental and epileptic encephalopathy, 21	5
NTRK2	Strong	Autosomal dominant	developmental and epileptic encephalopathy, 58	8
PARS2	Strong	Autosomal recessive	developmental and epileptic encephalopathy, 75	4
PPP3CA	Strong	Autosomal dominant	developmental and epileptic encephalopathy 91	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
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
SLC13A5	Orphanet:1946	Amelocerebrohypohidrotic syndrome
SLC13A5	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
SCN3A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
SCN3A	Orphanet:98820	Familial focal epilepsy with variable foci
SLC1A2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
STXBP1	Orphanet:495818	9q33.3q34.11 microdeletion syndrome
STXBP1	Orphanet:599373	STXBP1-related encephalopathy
SYNJ1	Orphanet:2828	Young-onset Parkinson disease
SYNJ1	Orphanet:391411	Atypical juvenile parkinsonism
SYNJ1	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
WWOX	Orphanet:251510	46,XY partial gonadal dysgenesis
WWOX	Orphanet:284282	Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to WWOX deficiency
WWOX	Orphanet:708171	Facial dysmorphism-corpus callosum hypoplasia-infantile epileptic encephalopathy
WWOX	Orphanet:99977	Squamous cell carcinoma of the esophagus
YWHAG	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
CYFIP2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
CACNA1B	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
ACTL6B	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
ACTL6B	Orphanet:528084	Non-specific syndromic intellectual disability
CDK19	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
CNKSR2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
CNKSR2	Orphanet:777	X-linked non-syndromic intellectual disability
AARS1	Orphanet:228174	Autosomal dominant Charcot-Marie-Tooth disease type 2N
AARS1	Orphanet:33364	Trichothiodystrophy
AARS1	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
DHDDS	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
DHDDS	Orphanet:791	Retinitis pigmentosa
CLTC	Orphanet:178342	Inflammatory myofibroblastic tumor
CLTC	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
CLTC	Orphanet:319308	MiT family translocation renal cell carcinoma
CLTC	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
NUS1	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
UBA5	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
NECAP1	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
CELF2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
DALRD3	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
SZT2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
DNM1	Orphanet:2382	Lennox-Gastaut syndrome
DNM1	Orphanet:442835	Non-specific early-onset epileptic encephalopathy

Cohort genes → proteins

48 cohort genes, 48 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	48

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCN8A	HGNC:10596	ENSG00000196876	Q9UQD0	Sodium channel protein type 8 subunit alpha	gencc,clinvar
CACNA1A	HGNC:1388	ENSG00000141837	O00555	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	gencc,clinvar
SLC13A5	HGNC:23089	ENSG00000141485	Q86YT5	Na(+)/citrate cotransporter	gencc,clinvar
SCN3A	HGNC:10590	ENSG00000153253	Q9NY46	Sodium channel protein type 3 subunit alpha	gencc
SLC1A2	HGNC:10940	ENSG00000110436	P43004	Excitatory amino acid transporter 2	gencc
STXBP1	HGNC:11444	ENSG00000136854	P61764	Syntaxin-binding protein 1	gencc
SYNJ1	HGNC:11503	ENSG00000159082	O43426	Synaptojanin-1	gencc
WWOX	HGNC:12799	ENSG00000186153	Q9NZC7	WW domain-containing oxidoreductase	gencc
YWHAG	HGNC:12852	ENSG00000170027	P61981	14-3-3 protein gamma	gencc
CYFIP2	HGNC:13760	ENSG00000055163	Q96F07	Cytoplasmic FMR1-interacting protein 2	gencc
CACNA1B	HGNC:1389	ENSG00000148408	Q00975	Voltage-dependent N-type calcium channel subunit alpha-1B	gencc
ACTL6B	HGNC:160	ENSG00000077080	O94805	Actin-like protein 6B	gencc
CDK19	HGNC:19338	ENSG00000155111	Q9BWU1	Cyclin-dependent kinase 19	gencc
CNKSR2	HGNC:19701	ENSG00000149970	Q8WXI2	Connector enhancer of kinase suppressor of ras 2	gencc
AARS1	HGNC:20	ENSG00000090861	P49588	Alanine–tRNA ligase, cytoplasmic	gencc
DHDDS	HGNC:20603	ENSG00000117682	Q86SQ9	Dehydrodolichyl diphosphate synthase complex subunit DHDDS	gencc
CLTC	HGNC:2092	ENSG00000141367	Q00610	Clathrin heavy chain 1	gencc
NUS1	HGNC:21042	ENSG00000153989	Q96E22	Dehydrodolichyl diphosphate synthase complex subunit NUS1	gencc
UBA5	HGNC:23230	ENSG00000081307	Q9GZZ9	Ubiquitin-like modifier-activating enzyme 5	gencc
NECAP1	HGNC:24539	ENSG00000089818	Q8NC96	Adaptin ear-binding coat-associated protein 1	gencc
CELF2	HGNC:2550	ENSG00000048740	O95319	CUGBP Elav-like family member 2	gencc
DALRD3	HGNC:25536	ENSG00000178149	Q5D0E6	DALR anticodon-binding domain-containing protein 3	gencc
SZT2	HGNC:29040	ENSG00000198198	Q5T011	KICSTOR complex protein SZT2	gencc
DNM1	HGNC:2972	ENSG00000106976	Q05193	Dynamin-1	gencc
TRAK1	HGNC:29947	ENSG00000182606	Q9UPV9	Trafficking kinesin-binding protein 1	gencc
PARS2	HGNC:30563	ENSG00000162396	Q7L3T8	Probable proline–tRNA ligase, mitochondrial	gencc
EEF1A2	HGNC:3192	ENSG00000101210	Q05639	Elongation factor 1-alpha 2	gencc
FGF12	HGNC:3668	ENSG00000114279	P61328	Fibroblast growth factor 12	gencc
FGF13	HGNC:3670	ENSG00000129682	Q92913	Fibroblast growth factor 13	gencc
GABRA2	HGNC:4076	ENSG00000151834	P47869	Gamma-aminobutyric acid receptor subunit alpha-2	gencc
GABRA5	HGNC:4079	ENSG00000186297	P31644	Gamma-aminobutyric acid receptor subunit alpha-5	gencc
GABRB2	HGNC:4082	ENSG00000145864	P47870	Gamma-aminobutyric acid receptor subunit beta-2	gencc
GABRG2	HGNC:4087	ENSG00000113327	P18507	Gamma-aminobutyric acid receptor subunit gamma-2	gencc
GRIN2D	HGNC:4588	ENSG00000105464	O15399	Glutamate receptor ionotropic, NMDA 2D	gencc
HCN1	HGNC:4845	ENSG00000164588	O60741	Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1	gencc
AP3B2	HGNC:567	ENSG00000103723	Q13367	AP-3 complex subunit beta-2	gencc
KCNA2	HGNC:6220	ENSG00000177301	P16389	Potassium voltage-gated channel subfamily A member 2	gencc
KCNB1	HGNC:6231	ENSG00000158445	Q14721	Potassium voltage-gated channel subfamily B member 1	gencc
NTRK2	HGNC:8032	ENSG00000148053	Q16620	BDNF/NT-3 growth factors receptor	gencc
ATP6V1A	HGNC:851	ENSG00000114573	P38606	V-type proton ATPase catalytic subunit A	gencc
PPP3CA	HGNC:9314	ENSG00000138814	Q08209	Protein phosphatase 3 catalytic subunit alpha	gencc
SCN1B	HGNC:10586	ENSG00000105711	Q07699	Sodium channel regulatory subunit beta-1	clinvar
SPTAN1	HGNC:11273	ENSG00000197694	Q13813	Spectrin alpha chain, non-erythrocytic 1	clinvar
RBFOX1	HGNC:18222	ENSG00000078328	Q9NWB1	RNA binding protein fox-1 homolog 1	clinvar
SRGAP2	HGNC:19751	ENSG00000266028	O75044	SLIT-ROBO Rho GTPase-activating protein 2	clinvar
IQSEC2	HGNC:29059	ENSG00000124313	Q5JU85	IQ motif and SEC7 domain-containing protein 2	clinvar
LIMK1	HGNC:6613	ENSG00000106683	P53667	LIM domain kinase 1	clinvar
ATP1A3	HGNC:801	ENSG00000105409	P13637	Sodium/potassium-transporting ATPase subunit alpha-3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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…
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…
SLC13A5	Na(+)/citrate cotransporter	High-affinity sodium/citrate cotransporter that mediates the entry of citrate into cells, which is a critical participant of biochemical pathways.
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.
SLC1A2	Excitatory amino acid transporter 2	Sodium-dependent, high-affinity amino acid transporter that mediates the uptake of L-glutamate and also L-aspartate and D-aspartate.
STXBP1	Syntaxin-binding protein 1	Participates in the regulation of synaptic vesicle docking and fusion through interaction with GTP-binding proteins.
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.
YWHAG	14-3-3 protein gamma	Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways.
CYFIP2	Cytoplasmic FMR1-interacting protein 2	Involved in T-cell adhesion and p53/TP53-dependent induction of apoptosis.
CACNA1B	Voltage-dependent N-type calcium channel subunit alpha-1B	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…
ACTL6B	Actin-like protein 6B	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
CNKSR2	Connector enhancer of kinase suppressor of ras 2	May function as an adapter protein or regulator of Ras signaling pathways.
AARS1	Alanine–tRNA ligase, cytoplasmic	Catalyzes the attachment of alanine to tRNA(Ala) in a two-step reaction: alanine is first activated by ATP to form Ala-AMP and then transferred to the acceptor end of tRNA(Ala).
DHDDS	Dehydrodolichyl diphosphate synthase complex subunit DHDDS	With NUS1, forms the dehydrodolichyl diphosphate synthase (DDS) complex, an essential component of the dolichol monophosphate (Dol-P) biosynthetic machinery.
CLTC	Clathrin heavy chain 1	Clathrin is the major protein of the polyhedral coat of coated pits and vesicles.
NUS1	Dehydrodolichyl diphosphate synthase complex subunit NUS1	With DHDDS, forms the dehydrodolichyl diphosphate synthase (DDS) complex, an essential component of the dolichol monophosphate (Dol-P) biosynthetic machinery.
UBA5	Ubiquitin-like modifier-activating enzyme 5	E1-like enzyme which specifically catalyzes the first step in ufmylation.
NECAP1	Adaptin ear-binding coat-associated protein 1	Involved in endocytosis.
CELF2	CUGBP Elav-like family member 2	RNA-binding protein implicated in the regulation of several post-transcriptional events.
DALRD3	DALR anticodon-binding domain-containing protein 3	Involved in tRNA methylation.
SZT2	KICSTOR complex protein SZT2	As part of the KICSTOR complex functions in the amino acid-sensing branch of the TORC1 signaling pathway.
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).
TRAK1	Trafficking kinesin-binding protein 1	Involved in the regulation of endosome-to-lysosome trafficking, including endocytic trafficking of EGF-EGFR complexes and GABA-A receptors.
PARS2	Probable proline–tRNA ligase, mitochondrial	Mitochondrial aminoacyl-tRNA synthetase that catalyzes the specific attachment of the proline amino acid (aa) to the homologous transfer RNA (tRNA), further participating in protein synthesis.
EEF1A2	Elongation factor 1-alpha 2	Translation elongation factor that catalyzes the GTP-dependent binding of aminoacyl-tRNA (aa-tRNA) to the A-site of ribosomes during the elongation phase of protein synthesis.
FGF12	Fibroblast growth factor 12	Involved in nervous system development and function.
FGF13	Fibroblast growth factor 13	Microtubule-binding protein which directly binds tubulin and is involved in both polymerization and stabilization of microtubules.
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.
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.
GABRB2	Gamma-aminobutyric acid receptor subunit beta-2	Beta 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.
GRIN2D	Glutamate receptor ionotropic, NMDA 2D	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+).
HCN1	Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1	Hyperpolarization-activated ion channel that are permeable to sodium and potassium ions.
AP3B2	AP-3 complex subunit beta-2	Subunit of non-clathrin- and clathrin-associated adaptor protein complex 3 (AP-3) that plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes.
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.
KCNB1	Potassium voltage-gated channel subfamily B member 1	Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain, but also in the pancreas and cardiovascular system.
NTRK2	BDNF/NT-3 growth factors receptor	Receptor tyrosine kinase involved in the development and the maturation of the central and the peripheral nervous systems through regulation of neuron survival, proliferation, migration, differentiation, and synapse formation and plasticit…
ATP6V1A	V-type proton ATPase catalytic subunit A	Catalytic subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons.
PPP3CA	Protein phosphatase 3 catalytic subunit alpha	Calcium-dependent, calmodulin-stimulated protein phosphatase which plays an essential role in the transduction of intracellular Ca(2+)-mediated signals.
SCN1B	Sodium channel regulatory subunit beta-1	Regulatory subunit of multiple voltage-gated sodium (Nav) channels directly mediating the depolarization of excitable membranes.
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.
RBFOX1	RNA binding protein fox-1 homolog 1	RNA-binding protein that regulates alternative splicing events by binding to 5’-UGCAUGU-3’ elements.
SRGAP2	SLIT-ROBO Rho GTPase-activating protein 2	Postsynaptic RAC1 GTPase activating protein (GAP) that plays a key role in neuronal morphogenesis and migration mainly during development of the cerebral cortex.
IQSEC2	IQ motif and SEC7 domain-containing protein 2	Is a guanine nucleotide exchange factor for the ARF GTP-binding proteins.
LIMK1	LIM domain kinase 1	Serine/threonine-protein kinase that plays an essential role in the regulation of actin filament dynamics.
ATP1A3	Sodium/potassium-transporting ATPase subunit alpha-3	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.

Protein-family classification

Druggable: 16 · Difficult: 7 · Unknown: 25 · Druggable fraction: 0.33

Family distribution

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

Family	Genes	Fold	FDR
Ion channel	7	16.3×	2e-06
Scaffold/PPI	6	2.2×	0.229
Kinase	3	1.7×	0.666
Phosphatase	1	1.8×	0.789
Antibody/Immunoglobulin	2	1.2×	0.789
Other/Unknown	25	0.9×	0.886
Enzyme (other)	3	0.8×	0.886
Transcription factor	1	0.2×	0.998

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCN8A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
CACNA1A	Ion channel	yes		VDCCAlpha1, CACNA1A, Ion_trans_dom
SLC13A5	Other/Unknown	no		SLC13A/DASS, Na/sul_symport_CS
SCN3A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_trans_assoc_dom
SLC1A2	Other/Unknown	no		Na-dicarboxylate_symporter, Na-dicarboxylate_symporter_CS, Na:dicarbo_symporter_sf
STXBP1	Other/Unknown	no		Sec1-like, Sec1-like_dom2, Sec1-like_sf
SYNJ1	Other/Unknown	no		IPPc, RRM_dom, SAC_dom
WWOX	Scaffold/PPI	no		WW_dom, SDR_fam, WW_dom_sf
YWHAG	Other/Unknown	no		14-3-3, 14-3-3_CS, 14-3-3_domain
CYFIP2	Other/Unknown	no		Cytoplasmic_FMR1-int, CYRIA/CYRIB_Rac1-bd
CACNA1B	Ion channel	yes		EF_hand_dom, VDCCAlpha1, VDCC_N_a1su
ACTL6B	Other/Unknown	no		Actin, Actin_CS, ATPase_NBD
CDK19	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
CNKSR2	Scaffold/PPI	no		PDZ, SAM, PH_domain
AARS1	Other/Unknown	no		Ala-tRNA-lgiase_IIc, DHHA1_dom, Transl_B-barrel_sf
DHDDS	Enzyme (other)	yes	2.5.1.87	UPP_synth-like, UPP_synth-like_CS, UPP_synth-like_sf
CLTC	Other/Unknown	no		Clathrin_H-chain/VPS_repeat, TPR-like_helical_dom_sf, Clathrin_H-chain_linker_core
NUS1	Enzyme (other)	yes	2.5.1.87	UPP_synth-like, UPP_synth-like_sf, Nus1/NgBR
UBA5	Enzyme (other)	yes	6.2.1.45	ThiF_NAD_FAD-bd, D-isomer_DH_CS1, Ubiquitin-activating_enz
NECAP1	Other/Unknown	no		PH-like_dom_sf, NECAP_PHear
CELF2	Other/Unknown	no		RRM_dom, Hud_Sxl_RNA, Nucleotide-bd_a/b_plait_sf
DALRD3	Other/Unknown	no		DALR_anticod-bd, tRNAsynth_Ia_anticodon-bd, DALRD3
SZT2	Other/Unknown	no		SZT2
DNM1	Scaffold/PPI	no	3.6.5.5	Dynamin_stalk, Dynamin_GTPase, PH_domain
TRAK1	Other/Unknown	no		HAP1_N, TRAK1/2_C, Intracell_Traff-Reg
PARS2	Other/Unknown	no		aa-tRNA-synt_IIb, Pro-tRNA-ligase_IIa, Anticodon-bd
EEF1A2	Other/Unknown	no		T_Tr_GTP-bd_dom, EFTu-like_2, Transl_elong_EF1A_euk/arc
FGF12	Other/Unknown	no		Fibroblast_GF_fam, IL1/FGF
FGF13	Other/Unknown	no		Fibroblast_GF_fam, IL1/FGF
GABRA2	Other/Unknown	no		GABAAa_rcpt, GABBAa2_rcpt, GABAA/Glycine_rcpt
GABRA5	Other/Unknown	no		GABAAa_rcpt, GABBAa5_rcpt, GABAA/Glycine_rcpt
GABRB2	Other/Unknown	no		GABAAb_rcpt, GABAA/Glycine_rcpt, Neurotrans-gated_channel_TM
GABRG2	Other/Unknown	no		GABRG-1/4, GABBAg2_rcpt, GABAA/Glycine_rcpt
GRIN2D	Other/Unknown	no		Iontro_rcpt_C, Iono_Glu_rcpt_met, ANF_lig-bd_rcpt
HCN1	Ion channel	yes		cNMP-bd_dom, K_chnl_volt-dep_EAG/ELK/ERG, Ion_trans_dom
AP3B2	Antibody/Immunoglobulin	yes		Clathrin/coatomer_adapt-like_N, ARM-like, Clathrin_app_Ig-like_sf
KCNA2	Ion channel	yes		BTB/POZ_dom, T1-type_BTB, K_chnl_volt-dep_Kv
KCNB1	Ion channel	yes		BTB/POZ_dom, T1-type_BTB, K_chnl_volt-dep_Kv
NTRK2	Kinase	yes	2.7.10.1	LRRNT, Cys-rich_flank_reg_C, Prot_kinase_dom
ATP6V1A	Other/Unknown	no		ATPase_F1/V1/A1_a/bsu_nucl-bd, ATPase_F1/V1/A1_a/bsu_N, ATPase_V1-cplx_asu
PPP3CA	Phosphatase	yes	3.1.3.16	Calcineurin-like_PHP, Ser/Thr-sp_prot-phosphatase, Metallo-depent_PP-like
SCN1B	Antibody/Immunoglobulin	yes		Ig_V-set, Ig-like_fold, Na_channel_b1/b3
SPTAN1	Scaffold/PPI	no		SH3_domain, Spectrin_repeat, EF_hand_dom
RBFOX1	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, RBFOX1-3
SRGAP2	Scaffold/PPI	no		RhoGAP_dom, FCH_dom, SH3_domain
IQSEC2	Scaffold/PPI	no		Sec7_dom, PH_domain, PH-like_dom_sf
LIMK1	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PDZ
ATP1A3	Transcription factor	no		P_typ_ATPase, ATPase_P-typ_cation-transptr_N, P-type_ATPase_IIC

Expression context

Cohort genes with no expression data: 0.

42 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)	48
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	14
middle temporal gyrus	10
cerebellar cortex	9
cerebellar hemisphere	9
right hemisphere of cerebellum	8
endothelial cell	8
cortical plate	6
lateral nuclear group of thalamus	6
postcentral gyrus	4
entorhinal cortex	3
pons	3
prefrontal cortex	3
primary visual cortex	3
parotid gland	2
cranial nerve II	2
frontal pole	2
CA1 field of hippocampus	2
oocyte	2
secondary oocyte	2
superior frontal gyrus	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCN8A	194	ubiquitous	marker	Brodmann (1909) area 23, middle temporal gyrus, postcentral gyrus
CACNA1A	237	broad	marker	cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex
SLC13A5	148	broad	yes	right lobe of liver, liver, parotid gland
SCN3A	221	broad	marker	endothelial cell, cortical plate, middle temporal gyrus
SLC1A2	227	broad	marker	endothelial cell, entorhinal cortex, Brodmann (1909) area 23
STXBP1	287	ubiquitous	marker	middle temporal gyrus, lateral nuclear group of thalamus, Brodmann (1909) area 23
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
YWHAG	266	ubiquitous	marker	lateral nuclear group of thalamus, pons, substantia nigra pars compacta
CYFIP2	286	ubiquitous	marker	renal medulla, middle temporal gyrus, saphenous vein
CACNA1B	146	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, postcentral gyrus
ACTL6B	164	broad	marker	cortical plate, right hemisphere of cerebellum, cerebellar hemisphere
CDK19	282	ubiquitous	marker	endothelial cell, medial globus pallidus, corpus callosum
CNKSR2	226	broad	marker	Brodmann (1909) area 23, cerebellar cortex, cerebellar hemisphere
AARS1	301	ubiquitous	marker	endometrium epithelium, type B pancreatic cell, frontal pole
DHDDS	259	ubiquitous	marker	sperm, cerebellar cortex, cerebellar hemisphere
CLTC	305	ubiquitous	marker	pons, lateral nuclear group of thalamus, Brodmann (1909) area 46
NUS1	255	broad	marker	endometrium, tibia, islet of Langerhans
UBA5	287	ubiquitous	marker	body of pancreas, right adrenal gland, right adrenal gland cortex
NECAP1	279	ubiquitous	marker	cortical plate, prefrontal cortex, cerebellar cortex
CELF2	289	ubiquitous	marker	CA1 field of hippocampus, orbitofrontal cortex, entorhinal cortex
DALRD3	266	ubiquitous	marker	left testis, right testis, right uterine tube
SZT2	238	ubiquitous	marker	colonic epithelium, sural nerve, granulocyte
DNM1	257	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
TRAK1	295	ubiquitous	marker	secondary oocyte, paraflocculus, oocyte
PARS2	193	ubiquitous	yes	secondary oocyte, oocyte, primordial germ cell in gonad
EEF1A2	247	ubiquitous	marker	gastrocnemius, apex of heart, hindlimb stylopod muscle
FGF12	204	broad	marker	right atrium auricular region, cardiac atrium, cardiac muscle of right atrium
FGF13	268	ubiquitous	marker	endothelial cell, dorsal root ganglion, cortical plate
GABRA2	195	broad	marker	frontal pole, entorhinal cortex, postcentral gyrus

Protein interactions among cohort

Intra-cohort edges: 28.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
WWOX	5,892
CLTC	5,550
NTRK2	5,190
ACTL6B	4,543
PPP3CA	4,486
ATP1A3	3,876
FGF13	3,763
YWHAG	3,643
DNM1	3,614
ATP6V1A	3,301

Intra-cohort edges

A	B	Sources
AP3B2	ATP1A3	string_interaction
AP3B2	HCN1	intact, string_interaction
ATP1A3	ATP6V1A	biogrid_interaction
ATP1A3	CLTC	biogrid_interaction
CLTC	DNM1	string_interaction
CLTC	NECAP1	intact
DHDDS	NUS1	biogrid_interaction, intact, string_interaction
DNM1	SYNJ1	string_interaction
EEF1A2	SLC13A5	biogrid_interaction, intact
GABRA2	GABRG2	biogrid_interaction
GABRB2	GABRG2	string_interaction
GABRB2	SCN1B	string_interaction
GABRG2	SCN1B	string_interaction
GABRG2	SCN8A	string_interaction
HCN1	KCNA2	string_interaction
HCN1	KCNB1	string_interaction
HCN1	SCN3A	intact
IQSEC2	STXBP1	string_interaction
IQSEC2	YWHAG	intact
KCNA2	KCNB1	string_interaction
KCNA2	SCN3A	string_interaction
KCNA2	SCN8A	string_interaction
KCNB1	SCN8A	string_interaction
SCN1B	SCN3A	string_interaction
SCN1B	SCN8A	string_interaction
SPTAN1	STXBP1	string_interaction
SRGAP2	YWHAG	intact
SYNJ1	YWHAG	intact

Structural data

PDB: 40 · AlphaFold-only: 8 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GABRG2	P18507	75
SCN1B	Q07699	39
GABRB2	P47870	31
GABRA5	P31644	23
YWHAG	P61981	22
DNM1	Q05193	22
PPP3CA	Q08209	21
HCN1	O60741	17
GRIN2D	O15399	13
UBA5	Q9GZZ9	12
CLTC	Q00610	10
LIMK1	P53667	10
DHDDS	Q86SQ9	9
NUS1	Q96E22	9
SZT2	Q5T011	9
NTRK2	Q16620	9
GABRA2	P47869	8
ATP6V1A	P38606	8
SCN8A	Q9UQD0	7
SLC1A2	P43004	7
CACNA1B	Q00975	7
CELF2	O95319	7
SPTAN1	Q13813	7
AARS1	P49588	6
KCNB1	Q14721	6
SRGAP2	O75044	6
SYNJ1	O43426	5
ATP1A3	P13637	5
CACNA1A	O00555	4
SLC13A5	Q86YT5	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACTL6B	O94805	91.52
DALRD3	Q5D0E6	88.57
PARS2	Q7L3T8	88.30
CYFIP2	Q96F07	87.28
KCNA2	P16389	78.01
CDK19	Q9BWU1	77.97
AP3B2	Q13367	75.73
TRAK1	Q9UPV9	59.19

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 233. Enrichment computed across 48 evidence-associated genes (44 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 44 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Phase 0 - rapid depolarisation	5	39.3×	3e-05	SCN8A, SCN1B, SCN3A, FGF12, FGF13
Interaction between L1 and Ankyrins	4	33.5×	7e-04	SCN8A, SCN1B, SCN3A, SPTAN1
GABA receptor activation	4	28.8×	8e-04	GABRA2, GABRA5, GABRB2, GABRG2
Defective DHDDS causes RP59	2	259.6×	8e-04	DHDDS, NUS1
Synthesis of dolichyl-phosphate	2	74.2×	0.013	DHDDS, NUS1
RHOU GTPase cycle	3	19.0×	0.013	SPTAN1, SRGAP2, CLTC
L1CAM interactions	4	10.9×	0.013	SCN8A, SCN1B, SCN3A, SPTAN1
Axon guidance	6	6.2×	0.013	SCN8A, SCN1B, SCN3A, SPTAN1, SRGAP2, LIMK1
Nervous system development	6	5.8×	0.013	SCN8A, SCN1B, SCN3A, SPTAN1, SRGAP2, LIMK1
Cardiac conduction	4	9.9×	0.016	SCN8A, SCN1B, SCN3A, ATP1A3
Formation of annular gap junctions	2	47.2×	0.017	CLTC, DNM1
Presynaptic depolarization and calcium channel opening	2	43.3×	0.017	CACNA1A, CACNA1B
Gap junction degradation	2	43.3×	0.017	CLTC, DNM1
Regulation of insulin secretion	3	15.0×	0.017	CACNA1A, STXBP1, KCNB1
Retrograde neurotrophin signalling	2	37.1×	0.020	CLTC, DNM1
Clathrin-mediated endocytosis	4	7.8×	0.025	SYNJ1, CLTC, NECAP1, DNM1
Integration of energy metabolism	3	12.0×	0.027	CACNA1A, STXBP1, KCNB1
Muscle contraction	4	7.0×	0.032	SCN8A, SCN1B, SCN3A, ATP1A3
Neuronal System	5	5.0×	0.037	CACNA1A, STXBP1, CACNA1B, KCNA2, KCNB1
Glutamate Neurotransmitter Release Cycle	2	20.8×	0.048	SLC1A2, STXBP1
Entry of Influenza Virion into Host Cell via Endocytosis	1	129.8×	0.072	CLTC
BDNF activates NTRK2 (TRKB) signaling	1	129.8×	0.072	NTRK2
NTF3 activates NTRK2 (TRKB) signaling	1	129.8×	0.072	NTRK2
NTF4 activates NTRK2 (TRKB) signaling	1	129.8×	0.072	NTRK2
Sensory perception of taste	2	15.3×	0.072	SCN1B, SCN3A
SLC-mediated transport of organic anions	1	86.5×	0.084	SLC13A5
tRNA Aminoacylation	2	13.0×	0.084	AARS1, PARS2
RHOV GTPase cycle	2	13.0×	0.084	SPTAN1, CLTC
Sensory perception of sweet, bitter, and umami (glutamate) taste	2	12.7×	0.084	SCN1B, SCN3A
Signaling by ERBB4	2	12.4×	0.084	GABRB2, GABRG2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 48 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
inhibitory synapse assembly	6	78.0×	5e-08	SRGAP2, FGF13, GABRA2, GABRA5, GABRB2, GABRG2
cardiac muscle cell action potential involved in contraction	4	58.5×	1e-04	SCN8A, SCN1B, SCN3A, FGF12
gamma-aminobutyric acid signaling pathway	4	45.3×	2e-04	GABRA2, GABRA5, GABRB2, GABRG2
synaptic transmission, GABAergic	4	41.3×	3e-04	GABRA2, GABRA5, GABRB2, GABRG2
dolichyl diphosphate biosynthetic process	2	351.1×	7e-04	DHDDS, NUS1
positive regulation of calcium ion-dependent exocytosis of neurotransmitter	2	234.1×	0.001	CACNA1B, PPP3CA
positive regulation of voltage-gated sodium channel activity	2	234.1×	0.001	SCN1B, FGF13
chloride transmembrane transport	4	19.8×	0.003	GABRA2, GABRA5, GABRB2, GABRG2
sodium ion transmembrane transport	4	16.9×	0.004	SCN8A, SCN1B, SCN3A, HCN1
cellular response to histamine	2	117.0×	0.005	GABRB2, GABRG2
modulation of chemical synaptic transmission	4	15.3×	0.005	CACNA1A, CACNA1B, IQSEC2, PPP3CA
inner ear receptor cell development	2	100.3×	0.006	GABRA5, GABRB2
dolichyl monophosphate biosynthetic process	2	78.0×	0.009	DHDDS, NUS1
positive regulation of long-term synaptic depression	2	78.0×	0.009	IQSEC2, KCNB1
membrane depolarization during action potential	2	70.2×	0.009	SCN1B, SCN3A
response to L-glutamate	2	70.2×	0.009	HCN1, KCNB1
action potential	3	22.4×	0.009	SCN8A, KCNA2, KCNB1
chemical synaptic transmission	5	8.1×	0.009	CACNA1A, SLC1A2, CACNA1B, FGF12, GABRB2
neuronal action potential propagation	2	58.5×	0.012	SCN1B, NTRK2
positive regulation of calcium ion-dependent exocytosis	2	54.0×	0.012	STXBP1, KCNB1
nervous system development	6	5.7×	0.012	ACTL6B, RBFOX1, SRGAP2, FGF12, FGF13, LIMK1
learning	3	17.6×	0.013	SYNJ1, FGF13, NTRK2
sodium ion transport	3	17.0×	0.014	SCN8A, SCN3A, FGF13
potassium ion export across plasma membrane	2	43.9×	0.016	KCNA2, KCNB1
regulation of sodium ion transmembrane transport	2	43.9×	0.016	SCN1B, FGF12
response to amyloid-beta	2	41.3×	0.017	CACNA1A, CACNA1B
innervation	2	37.0×	0.021	GABRA5, GABRB2
positive regulation of sodium ion transport	2	35.1×	0.022	SCN1B, FGF12
synaptic vesicle priming	2	33.4×	0.023	STXBP1, SYNJ1
neurogenesis	3	13.0×	0.023	TRAK1, FGF12, FGF13

Therapeutics

Drug target analysis

Approved (phase 4): 16 · Phase ≥3: 18 · Phased (≥1): 21 · Undrugged: 27

Druggability breadth: 33 of 48 evidence-associated genes (69%) 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
SCN8A	IMIPRAMINE
CACNA1A	NIMODIPINE
SCN3A	BEPRIDIL
SYNJ1	PYRVINIUM
CACNA1B	NIFEDIPINE
CDK19	SORAFENIB
DNM1	CETRIMIDE
GABRA2	ENZALUTAMIDE
GABRA5	ENZALUTAMIDE
GABRB2	CANNABIDIOL
GABRG2	ENZALUTAMIDE
GRIN2D	DEXTROMETHORPHAN
NTRK2	FEDRATINIB
PPP3CA	ZINC CHLORIDE
LIMK1	FEDRATINIB
ATP1A3	OMEPRAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN3A	93	4
GABRG2	55	4
NTRK2	50	4
GABRB2	47	4
GABRA2	46	4
LIMK1	38	4
GRIN2D	29	4
GABRA5	27	4
SCN8A	25	4
CACNA1B	23	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IMIPRAMINE	4	CACNA1B, SCN3A, SCN8A
SERTINDOLE	4	SCN3A, SCN8A
PIMOZIDE	4	SCN3A, SCN8A
NIFEDIPINE	4	CACNA1B, SCN3A, SCN8A
DILTIAZEM	4	SCN3A, SCN8A
MIBEFRADIL	4	CACNA1B, SCN3A, SCN8A
HALOPERIDOL	4	SCN3A, SCN8A
MEXILETINE	4	SCN3A, SCN8A
AMITRIPTYLINE	4	CACNA1B, SCN3A, SCN8A
AMIODARONE	4	SCN3A, SCN8A
CHLORPROMAZINE	4	GRIN2D, SCN3A, SCN8A
TETRACAINE	4	SCN3A, SCN8A
NIMODIPINE	4	CACNA1A, CACNA1B
TACRINE	4	CACNA1A, CACNA1B
BEPRIDIL	4	SCN3A
DIBUCAINE	4	SCN3A
ARTICAINE	4	SCN3A
BUPIVACAINE	4	SCN3A
DROPERIDOL	4	SCN3A
DICYCLOMINE	4	SCN3A
TETRABENAZINE	4	SCN3A
PHENIRAMINE	4	SCN3A
PRILOCAINE	4	SCN3A
PROPOXYCAINE	4	SCN3A
PROPARACAINE	4	SCN3A
HEXYLCAINE	4	SCN3A
PRAMOXINE	4	SCN3A
BENOXINATE	4	SCN3A
QUINIDINE	4	SCN3A
FELODIPINE	4	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
GABRG2	1,155	Binding:940, Functional:201, ADMET:10, Toxicity:4
NTRK2	554	Binding:547, ADMET:5, Functional:2
GABRB2	549	Binding:463, Functional:81, Toxicity:4, ADMET:1
GABRA5	413	Binding:352, Functional:57, Toxicity:3, ADMET:1
GABRA2	385	Binding:327, Functional:52, ADMET:3, Toxicity:3
LIMK1	307	Binding:306, Functional:1
GRIN2D	227	Binding:214, Functional:8, ADMET:4, Toxicity:1
CDK19	210	Binding:209, Functional:1
SCN8A	173	Binding:148, Functional:16, ADMET:7, Toxicity:2
CACNA1B	135	Binding:110, Functional:25
SCN3A	102	Binding:79, Functional:18, ADMET:4, Toxicity:1
SLC1A2	90	Binding:84, Functional:6
ATP1A3	45	Binding:45
KCNA2	36	Binding:31, Functional:3, ADMET:1, Toxicity:1
KCNB1	28	Binding:27, Toxicity:1
PPP3CA	24	Binding:24
HCN1	21	Binding:12, Functional:8, ADMET:1
CACNA1A	19	Binding:18, Functional:1
SCN1B	15	Binding:7, ADMET:6, Toxicity:2
SLC13A5	14	Binding:11, Functional:3
YWHAG	12	Binding:11, Functional:1
DNM1	11	Binding:11
CLTC	8	Binding:8
EEF1A2	8	Binding:8
SPTAN1	7	Binding:7
SYNJ1	2	Binding:2
AARS1	2	Binding:2
UBA5	2	Binding:2
ATP6V1A	2	Binding:2
STXBP1	1	Binding:1
CYFIP2	1	Binding:1
CNKSR2	1	Binding:1
CELF2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DHDDS	2.5.1.87	ditrans,polycis-polyprenyl diphosphate synthase [(2E,6E)-farnesyl diphosphate specific]
NUS1	2.5.1.87	ditrans,polycis-polyprenyl diphosphate synthase [(2E,6E)-farnesyl diphosphate specific]
UBA5	6.2.1.45	E1 ubiquitin-activating enzyme
DNM1	3.6.5.5	dynamin GTPase
NTRK2	2.7.10.1	receptor protein-tyrosine kinase
PPP3CA	3.1.3.16	protein-serine/threonine phosphatase
LIMK1	2.7.11.1	non-specific serine/threonine protein kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN8A	173
SCN3A	102
CACNA1B	135
CDK19	210
GABRA2	385
GABRA5	413
GABRB2	549
GABRG2	1,155
GRIN2D	227
NTRK2	554
LIMK1	307

Pharmacogenomics

Cohort genes with a PharmGKB record: 48; 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)
IMIPRAMINE	4	CACNA1B, SCN3A, SCN8A
SERTINDOLE	4	SCN3A, SCN8A
PIMOZIDE	4	SCN3A, SCN8A
NIFEDIPINE	4	CACNA1B, SCN3A, SCN8A
DILTIAZEM	4	SCN3A, SCN8A
MIBEFRADIL	4	CACNA1B, SCN3A, SCN8A
HALOPERIDOL	4	SCN3A, SCN8A
MEXILETINE	4	SCN3A, SCN8A
AMITRIPTYLINE	4	CACNA1B, SCN3A, SCN8A
AMIODARONE	4	SCN3A, SCN8A
CHLORPROMAZINE	4	GRIN2D, SCN3A, SCN8A
TETRACAINE	4	SCN3A, SCN8A
NIMODIPINE	4	CACNA1A, CACNA1B
TACRINE	4	CACNA1A, CACNA1B
BEPRIDIL	4	SCN3A
DIBUCAINE	4	SCN3A
ARTICAINE	4	SCN3A
BUPIVACAINE	4	SCN3A
DROPERIDOL	4	SCN3A
DICYCLOMINE	4	SCN3A
TETRABENAZINE	4	SCN3A
PHENIRAMINE	4	SCN3A
PRILOCAINE	4	SCN3A
PROPOXYCAINE	4	SCN3A
PROPARACAINE	4	SCN3A
HEXYLCAINE	4	SCN3A
PRAMOXINE	4	SCN3A
BENOXINATE	4	SCN3A
QUINIDINE	4	SCN3A
FELODIPINE	4	SCN3A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	16	SCN8A, CACNA1A, SCN3A, SYNJ1, CACNA1B, CDK19, DNM1, GABRA2, GABRA5, GABRB2 (+6 more)
B	Phased (≥1) drug, not yet approved	5	SLC1A2, YWHAG, KCNA2, SCN1B, SPTAN1
C	Druggable family + PDB, no drug	5	DHDDS, NUS1, UBA5, HCN1, KCNB1
D	Druggable family + AlphaFold only, no drug	1	AP3B2
E	Difficult family or no structure, no drug	21	SLC13A5, STXBP1, WWOX, CYFIP2, ACTL6B, CNKSR2, AARS1, CLTC, NECAP1, CELF2 (+11 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HCN1	21	KCNA2
KCNB1	28	KCNA2
SLC13A5	14	—
STXBP1	1	—
WWOX	0	—
CYFIP2	1	—
ACTL6B	0	—
CNKSR2	1	—
AARS1	2	—
DHDDS	0	—
CLTC	8	—
NUS1	0	—
UBA5	2	—
NECAP1	0	—
CELF2	1	—
DALRD3	0	—
SZT2	0	—
TRAK1	0	—
PARS2	0	—
EEF1A2	8	—
FGF12	0	—
FGF13	0	—
AP3B2	0	—
ATP6V1A	2	—
RBFOX1	0	—
SRGAP2	0	—
IQSEC2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.