Generalized epilepsy with febrile seizures plus

Summary

Generalized epilepsy with febrile seizures plus (MONDO:0018214) is a disease (an umbrella term covering 10 Mondo subtypes) caused by SCN1A (GenCC Strong), with 11 cohort genes. The dominant Reactome pathway is Interaction between L1 and Ankyrins (4 cohort genes).

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: SCN1A (GenCC Strong)
• Umbrella term: 10 Mondo subtypes
• Cohort genes: 11
• ClinVar variants: 32
• Phenotypes (HPO): 28

Clinical features

Signs & symptoms

Clinical features (HPO)

28 HPO clinical features (Orphanet curated; top 28 by frequency):

HPO ID	Term	Frequency
HP:0002197	Generalized-onset seizure	Very frequent (80-99%)
HP:0002121	Generalized non-motor (absence) seizure	Frequent (30-79%)
HP:0002373	Febrile seizure (within the age range of 3 months to 6 years)	Frequent (30-79%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0002069	Bilateral tonic-clonic seizure	Occasional (5-29%)
HP:0002123	Generalized myoclonic seizure	Occasional (5-29%)
HP:0002311	Incoordination	Occasional (5-29%)
HP:0002376	Developmental regression	Occasional (5-29%)
HP:0002539	Cortical dysplasia	Occasional (5-29%)
HP:0007010	Poor fine motor coordination	Occasional (5-29%)
HP:0007058	Generalized cerebral atrophy/hypoplasia	Occasional (5-29%)
HP:0010819	Atonic seizure	Occasional (5-29%)
HP:0010850	EEG with spike-wave complexes	Occasional (5-29%)
HP:0011151	Obtundation status	Occasional (5-29%)
HP:0100543	Cognitive impairment	Occasional (5-29%)
HP:0000729	Autistic behavior	Very rare (<1-4%)
HP:0000739	Anxiety	Very rare (<1-4%)
HP:0001337	Tremor	Very rare (<1-4%)
HP:0001763	Pes planus	Very rare (<1-4%)
HP:0002067	Bradykinesia	Very rare (<1-4%)
HP:0002133	Status epilepticus	Very rare (<1-4%)
HP:0002384	Focal impaired awareness seizure	Very rare (<1-4%)
HP:0003066	Limited knee extension	Very rare (<1-4%)
HP:0004684	Talipes valgus	Very rare (<1-4%)
HP:0007359	Focal-onset seizure	Very rare (<1-4%)
HP:0008770	Obsessive-compulsive trait	Very rare (<1-4%)
HP:0100694	Tibial torsion	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	generalized epilepsy with febrile seizures plus
Mondo ID	MONDO:0018214
MeSH	C565808
OMIM	604233
Orphanet	36387
DOID	DOID:0060170
NCIT	C122811
SNOMED CT	699688008
UMLS	C3502809
MedGen	503203
GARD	0018641
Is cancer (heuristic)	no

Also known as: epilepsy, generalized, with febrile seizures plus · GEFS+ · generalised epilepsy with febrile seizures-plus · generalized epilepsy with febrile seizures plus · genetic epilepsy with febrile seizures plus · genetic epilepsy with febrile seizures-plus

Data availability: 32 ClinVar variants · 7 ClinGen variant curations · 6 GenCC gene-disease records · 10 cell lines.

Disease family

An umbrella term covering 10 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neurological disease › hereditary generalized epilepsy › generalized epilepsy with febrile seizures plus

Related subtypes (1): idiopathic generalized epilepsy

Subtypes (10): generalized epilepsy with febrile seizures plus, type 1, generalized epilepsy with febrile seizures plus, type 2, febrile seizures, familial, 8, generalized epilepsy with febrile seizures plus, type 4, generalized epilepsy with febrile seizures plus, type 6, generalized epilepsy with febrile seizures plus, type 8, generalized epilepsy with febrile seizures plus, type 7, generalized epilepsy with febrile seizures plus, type 9, generalized epilepsy with febrile seizures plus, type 10, generalized epilepsy with febrile seizures plus, type 12

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

32 retrieved; paginated sample, class counts are floors:

15 uncertain significance, 4 pathogenic, 4 pathogenic/likely pathogenic, 3 likely pathogenic, 3 likely benign, 2 benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
3067136	NM_001286615.2(ANO4):c.1582G>A (p.Val528Met)	ANO4	Pathogenic	criteria provided, single submitter
972887	NM_001165963.4(SCN1A):c.345T>A (p.Asn115Lys)	SCN1A	Pathogenic	criteria provided, multiple submitters, no conflicts
471143	NM_001365536.1(SCN9A):c.5351del (p.Glu1784fs)	SCN1A-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1342700	NM_001040142.2(SCN2A):c.1528_1533del (p.Gln510_Lys511del)	SCN2A	Pathogenic	no assertion criteria provided
421969	NM_001365536.1(SCN9A):c.2719C>T (p.Arg907Trp)	SCN9A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
918042	NM_080552.3(SLC32A1):c.1403T>C (p.Leu468Pro)	SLC32A1	Pathogenic/Likely pathogenic	no assertion criteria provided
918043	NM_080552.3(SLC32A1):c.989T>C (p.Met330Thr)	SLC32A1	Pathogenic/Likely pathogenic	no assertion criteria provided
1326264	NM_052874.5(STX1B):c.286G>T (p.Glu96Ter)	STX1B	Pathogenic	no assertion criteria provided
658067	NM_001165963.4(SCN1A):c.3629C>T (p.Thr1210Met)	LOC102724058	Likely pathogenic	reviewed by expert panel
189996	NM_001165963.4(SCN1A):c.1259C>T (p.Ala420Val)	SCN1A	Likely pathogenic	reviewed by expert panel
374331	NM_001165963.4(SCN1A):c.1709G>A (p.Ser570Asn)	SCN1A	Likely pathogenic	reviewed by expert panel
130208	NM_001165963.4(SCN1A):c.5797del (p.Arg1933fs)	LOC102724058	Uncertain significance	reviewed by expert panel
1693292	NM_001165963.4(SCN1A):c.2636T>C (p.Leu879Pro)	SCN1A	Uncertain significance	criteria provided, single submitter
372977	NM_001165963.4(SCN1A):c.2941C>A (p.Leu981Ile)	SCN1A	Uncertain significance	reviewed by expert panel
1048116	NM_001365536.1(SCN9A):c.1465T>G (p.Ser489Ala)	SCN1A-AS1	Uncertain significance	criteria provided, single submitter
1300405	NM_001365536.1(SCN9A):c.3301A>G (p.Met1101Val)	SCN1A-AS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2123172	NM_001365536.1(SCN9A):c.1312G>A (p.Glu438Lys)	SCN1A-AS1	Uncertain significance	criteria provided, single submitter
433099	NM_001365536.1(SCN9A):c.1846G>A (p.Gly616Arg)	SCN1A-AS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
451326	NM_001365536.1(SCN9A):c.2299C>A (p.Pro767Thr)	SCN1A-AS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1053830	NM_001365536.1(SCN9A):c.3332A>G (p.Asp1111Gly)	SCN9A	Uncertain significance	criteria provided, single submitter
918044	NM_080552.3(SLC32A1):c.1391C>G (p.Thr464Arg)	SLC32A1	Uncertain significance	criteria provided, single submitter
918045	NM_080552.3(SLC32A1):c.788T>C (p.Val263Ala)	SLC32A1	Uncertain significance	no assertion criteria provided
918046	NM_080552.3(SLC32A1):c.1382G>A (p.Gly461Asp)	SLC32A1	Uncertain significance	criteria provided, single submitter
918047	NM_080552.3(SLC32A1):c.1393G>A (p.Gly465Ser)	SLC32A1	Uncertain significance	no assertion criteria provided
918048	NM_080552.3(SLC32A1):c.1333C>T (p.Leu445Phe)	SLC32A1	Uncertain significance	no assertion criteria provided
918049	NM_080552.3(SLC32A1):c.127G>T (p.Gly43Cys)	SLC32A1	Uncertain significance	no assertion criteria provided
36753	NM_001165963.4(SCN1A):c.3199G>A (p.Ala1067Thr)	LOC102724058	Benign	criteria provided, multiple submitters, no conflicts
283885	NM_001165963.4(SCN1A):c.1678C>T (p.Arg560Cys)	SCN1A	Likely benign	reviewed by expert panel
36752	NM_001165963.4(SCN1A):c.2292T>C (p.Val764=)	SCN1A	Benign	criteria provided, multiple submitters, no conflicts
93664	NM_001165963.4(SCN1A):c.83G>A (p.Arg28His)	SCN1A	Likely benign	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 57 · Orphanet: 39 · 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
GABRG2	Definitive	Autosomal dominant	epilepsy	11
SCN1A	Definitive	Autosomal dominant	generalized epilepsy with febrile seizures plus, type 2	20
SCN1B	Definitive	Autosomal dominant	generalized epilepsy with febrile seizures plus, type 1	15
HCN1	Strong	Autosomal dominant	generalized epilepsy with febrile seizures plus, type 10	7
STX1B	Strong	Autosomal dominant	generalized epilepsy with febrile seizures plus, type 9	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SCN1A	Orphanet:1942	Epilepsy with myoclonic-atonic seizures
SCN1A	Orphanet:2382	Lennox-Gastaut syndrome
SCN1A	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
SCN1A	Orphanet:33069	Dravet syndrome
SCN1A	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN1A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
SCN1A	Orphanet:569	Familial or sporadic hemiplegic migraine
STX1B	Orphanet:36387	Genetic epilepsy with febrile seizure plus
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
GABRG2	Orphanet:1945	Self-limited epilepsy with centrotemporal spikes
GABRG2	Orphanet:33069	Dravet syndrome
GABRG2	Orphanet:36387	Genetic epilepsy with febrile seizure plus
GABRG2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
GABRG2	Orphanet:64280	Childhood absence epilepsy
HCN1	Orphanet:36387	Genetic epilepsy with febrile seizure plus
HCN1	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
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
SCN9A	Orphanet:306577	Hereditary sodium channelopathy-related small fibers neuropathy
SCN9A	Orphanet:33069	Dravet syndrome
SCN9A	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN9A	Orphanet:46348	Paroxysmal extreme pain disorder
SCN9A	Orphanet:88642	Congenital insensitivity to pain-anosmia-neuropathic arthropathy
SCN9A	Orphanet:90026	Primary erythromelalgia
SCN9A	Orphanet:970	Hereditary sensory and autonomic neuropathy type 2
SLC32A1	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
SLC32A1	Orphanet:36387	Genetic epilepsy with febrile seizure plus
ATP10A	Orphanet:411515	Angelman syndrome due to imprinting defect in 15q11-q13

Cohort genes → proteins

11 cohort genes, 10 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	11

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCN1A	HGNC:10585	ENSG00000144285	P35498	Sodium channel protein type 1 subunit alpha	gencc,clinvar
STX1B	HGNC:18539	ENSG00000099365	P61266	Syntaxin-1B	gencc,clinvar
SCN1B	HGNC:10586	ENSG00000105711	Q07699	Sodium channel regulatory subunit beta-1	gencc
GABRG2	HGNC:4087	ENSG00000113327	P18507	Gamma-aminobutyric acid receptor subunit gamma-2	gencc
HCN1	HGNC:4845	ENSG00000164588	O60741	Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1	gencc
SCN2A	HGNC:10588	ENSG00000136531	Q99250	Sodium channel protein type 2 subunit alpha	clinvar
SCN9A	HGNC:10597	ENSG00000169432	Q15858	Sodium channel protein type 9 subunit alpha	clinvar
SLC32A1	HGNC:11018	ENSG00000101438	Q9H598	Vesicular inhibitory amino acid transporter	clinvar
ATP10A	HGNC:13542	ENSG00000206190	O60312	Phospholipid-transporting ATPase VA	clinvar
ANO4	HGNC:23837	ENSG00000151572	Q32M45	Anoctamin-4	clinvar
SCN1A-AS1	HGNC:54069	ENSG00000236107		SCN1A and SCN9A antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCN1A	Sodium channel protein type 1 subunit alpha	Pore-forming subunit of Nav1.1, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
STX1B	Syntaxin-1B	Potentially involved in docking of synaptic vesicles at presynaptic active zones.
SCN1B	Sodium channel regulatory subunit beta-1	Regulatory subunit of multiple voltage-gated sodium (Nav) channels directly mediating the depolarization of excitable membranes.
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.
HCN1	Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1	Hyperpolarization-activated ion channel that are permeable to sodium and potassium ions.
SCN2A	Sodium channel protein type 2 subunit alpha	Mediates the voltage-dependent sodium ion permeability of excitable membranes.
SCN9A	Sodium channel protein type 9 subunit alpha	Pore-forming subunit of Nav1.7, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
SLC32A1	Vesicular inhibitory amino acid transporter	Antiporter that exchanges vesicular protons for cytosolic 4-aminobutanoate or to a lesser extend glycine, thus allowing their secretion from nerve terminals.
ATP10A	Phospholipid-transporting ATPase VA	Catalytic component of P4-ATPase flippase complex, which catalyzes the hydrolysis of ATP coupled to the transport of phosphatidylcholine (PC) from the outer to the inner leaflet of the plasma membrane.
ANO4	Anoctamin-4	Has calcium-dependent phospholipid scramblase activity; scrambles phosphatidylserine, phosphatidylcholine and galactosylceramide.

Protein-family classification

Druggable: 5 · Difficult: 1 · Unknown: 5 · Druggable fraction: 0.45

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	4	40.6×	8e-06
Antibody/Immunoglobulin	1	2.6×	0.637
Other/Unknown	5	0.8×	0.840
Transcription factor	1	0.8×	0.840

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCN1A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a1su
STX1B	Other/Unknown	no		T_SNARE_dom, Syntaxin_N, Syntaxin/epimorphin_CS
SCN1B	Antibody/Immunoglobulin	yes		Ig_V-set, Ig-like_fold, Na_channel_b1/b3
GABRG2	Other/Unknown	no		GABRG-1/4, GABBAg2_rcpt, GABAA/Glycine_rcpt
HCN1	Ion channel	yes		cNMP-bd_dom, K_chnl_volt-dep_EAG/ELK/ERG, Ion_trans_dom
SCN2A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
SCN9A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
SLC32A1	Other/Unknown	no		AA_transpt_TM
ATP10A	Transcription factor	no	7.6.2.1	P_typ_ATPase, P-type_ATPase_IV, ATPase_P-typ_transduc_dom_A_sf
ANO4	Other/Unknown	no		Anoctamin, Anoct_dimer, Anoctamin_TM
SCN1A-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

11 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)	11
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	4
primary visual cortex	3
right hemisphere of cerebellum	2
middle temporal gyrus	2
endothelial cell	2
sural nerve	2
male germ line stem cell (sensu Vertebrata) in testis	2
lateral nuclear group of thalamus	1
cerebellar cortex	1
cerebellar hemisphere	1
cerebellum	1
superior frontal gyrus	1
cerebellar vermis	1
dorsal root ganglion	1
stromal cell of endometrium	1
nucleus accumbens	1
prefrontal cortex	1
putamen	1
descending thoracic aorta	1
thoracic aorta	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCN1A	154	tissue_specific	marker	Brodmann (1909) area 23, lateral nuclear group of thalamus, primary visual cortex
STX1B	176	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
SCN1B	133	ubiquitous	marker	primary visual cortex, right hemisphere of cerebellum, cerebellum
GABRG2	174	tissue_specific	marker	middle temporal gyrus, Brodmann (1909) area 23, superior frontal gyrus
HCN1	147	broad	marker	endothelial cell, Brodmann (1909) area 23, primary visual cortex
SCN2A	187	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, cerebellar vermis
SCN9A	187	ubiquitous	marker	sural nerve, dorsal root ganglion, stromal cell of endometrium
SLC32A1	69	broad	marker	nucleus accumbens, putamen, prefrontal cortex
ATP10A	229	broad	marker	endothelial cell, descending thoracic aorta, thoracic aorta
ANO4	126	broad	marker	corpus callosum, cortical plate, male germ line stem cell (sensu Vertebrata) in testis
SCN1A-AS1	129	tissue_specific	marker	sural nerve, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 11.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC32A1	3,331
SCN2A	2,810
GABRG2	2,392
SCN1A	2,287
STX1B	2,130
SCN9A	1,575
SCN1B	1,328
ATP10A	1,016
HCN1	726
ANO4	673

Intra-cohort edges

A	B	Sources
GABRG2	SCN1A	string_interaction
GABRG2	SCN1B	string_interaction
GABRG2	SCN2A	string_interaction
GABRG2	SCN9A	string_interaction
HCN1	SCN2A	intact
HCN1	SCN9A	intact
SCN1A	SCN1B	biogrid_interaction, string_interaction
SCN1A	SCN2A	biogrid_interaction, string_interaction
SCN1B	SCN2A	string_interaction
SCN1B	SCN9A	string_interaction
SCN2A	SCN9A	intact

Structural data

PDB: 6 · AlphaFold-only: 4 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GABRG2	P18507	75
SCN9A	Q15858	43
SCN1B	Q07699	39
HCN1	O60741	17
SCN2A	Q99250	5
SCN1A	P35498	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
STX1B	P61266	84.17
ANO4	Q32M45	79.27
SLC32A1	Q9H598	78.69
ATP10A	O60312	71.30

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 32. Enrichment computed across 11 evidence-associated genes (10 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 10 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	4	147.3×	2e-07	SCN1A, SCN1B, SCN2A, SCN9A
Phase 0 - rapid depolarisation	4	138.4×	2e-07	SCN1A, SCN1B, SCN2A, SCN9A
L1CAM interactions	4	48.1×	1e-05	SCN1A, SCN1B, SCN2A, SCN9A
Cardiac conduction	4	43.5×	1e-05	SCN1A, SCN1B, SCN2A, SCN9A
Sensory perception of taste	3	100.8×	2e-05	SCN1B, SCN2A, SCN9A
Sensory perception of sweet, bitter, and umami (glutamate) taste	3	83.6×	2e-05	SCN1B, SCN2A, SCN9A
Muscle contraction	4	30.9×	2e-05	SCN1A, SCN1B, SCN2A, SCN9A
Axon guidance	4	18.1×	2e-04	SCN1A, SCN1B, SCN2A, SCN9A
Nervous system development	4	17.2×	2e-04	SCN1A, SCN1B, SCN2A, SCN9A
Sensory Perception	3	28.6×	4e-04	SCN1B, SCN2A, SCN9A
Developmental Biology	5	7.2×	9e-04	SCN1A, STX1B, SCN1B, SCN2A, SCN9A
Toxicity of botulinum toxin type C (botC)	1	380.7×	0.007	STX1B
HCN channels	1	285.5×	0.009	HCN1
Ion channel transport	2	19.2×	0.010	ATP10A, ANO4
Neurotoxicity of clostridium toxins	1	142.8×	0.015	STX1B
Induction of Cell-Cell Fusion	1	87.8×	0.022	ANO4
Uptake and actions of bacterial toxins	1	81.6×	0.022	STX1B
LGI-ADAM interactions	1	81.6×	0.022	STX1B
GABA synthesis, release, reuptake and degradation	1	63.4×	0.026	SLC32A1
SLC-mediated transport of neurotransmitters	1	40.8×	0.039	SLC32A1
Bacterial Infection Pathways	1	33.6×	0.045	STX1B
GABA receptor activation	1	31.7×	0.045	GABRG2
Late SARS-CoV-2 Infection Events	1	29.3×	0.047	ANO4
Signaling by ERBB4	1	27.2×	0.048	GABRG2
Ion transport by P-type ATPases	1	20.8×	0.060	ATP10A
Transport of small molecules	2	5.0×	0.070	ATP10A, ANO4
Infectious disease	2	5.0×	0.070	STX1B, ANO4
Stimuli-sensing channels	1	13.6×	0.081	ANO4
SARS-CoV-2 Infection	1	8.0×	0.130	ANO4
SARS-CoV Infections	1	5.5×	0.178	ANO4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 10 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	280.9×	3e-08	SCN1A, SCN1B, SCN2A, SCN9A
sodium ion transmembrane transport	5	101.5×	3e-08	SCN1A, SCN1B, SCN2A, SCN9A, HCN1
neuronal action potential	4	192.6×	1e-07	SCN1A, SCN2A, SCN9A, HCN1
membrane depolarization during action potential	2	337.0×	4e-04	SCN1A, SCN1B
neuronal action potential propagation	2	280.9×	4e-04	SCN1A, SCN1B
corticospinal neuron axon guidance	1	1685.2×	0.005	SCN1B
action potential propagation	1	1685.2×	0.005	SCN9A
positive regulation of membrane hyperpolarization	1	1685.2×	0.005	HCN1
negative regulation of synaptic vesicle recycling	1	1685.2×	0.005	STX1B
positive regulation of spontaneous neurotransmitter secretion	1	1685.2×	0.005	STX1B
negative regulation of macropinocytosis	1	1685.2×	0.005	STX1B
regulation of heart rate by cardiac conduction	2	74.9×	0.005	SCN1B, HCN1
sodium ion transport	2	54.4×	0.005	SCN1A, SCN2A
chloride transmembrane transport	2	47.5×	0.005	ANO4, GABRG2
beta-alanine transport	1	842.6×	0.006	SLC32A1
intrinsic apoptotic signaling pathway in response to osmotic stress	1	842.6×	0.006	SCN2A
gamma-aminobutyric acid transport	1	842.6×	0.006	SLC32A1
monoatomic ion transmembrane transport	2	41.6×	0.006	ATP10A, ANO4
post-embryonic development	2	41.1×	0.006	SCN9A, GABRG2
calcium activated galactosylceramide scrambling	1	561.7×	0.007	ANO4
membrane depolarization during Purkinje myocyte cell action potential	1	561.7×	0.007	SCN1B
positive regulation of membrane tubulation	1	561.7×	0.007	ATP10A
positive regulation of voltage-gated sodium channel activity	1	561.7×	0.007	SCN1B
establishment of localization in cell	2	32.1×	0.007	SCN1A, ANO4
negative regulation of action potential	1	421.3×	0.008	HCN1
calcium ion-regulated exocytosis of neurotransmitter	1	421.3×	0.008	STX1B
regulation of synaptic activity	1	421.3×	0.008	STX1B
calcium activated phosphatidylserine scrambling	1	421.3×	0.008	ANO4
general adaptation syndrome, behavioral process	1	337.0×	0.010	HCN1
calcium activated phosphatidylcholine scrambling	1	337.0×	0.010	ANO4

Therapeutics

Drug target analysis

Approved (phase 4): 4 · Phase ≥3: 4 · Phased (≥1): 5 · Undrugged: 6

Druggability breadth: 6 of 11 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
GABRG2	ENZALUTAMIDE
SCN2A	BEPRIDIL
SCN9A	IMIPRAMINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN2A	99	4
SCN1A	94	4
GABRG2	55	4
SCN9A	36	4
SCN1B	2	2
STX1B	0	0
HCN1	0	0
SLC32A1	0	0
ATP10A	0	0
ANO4	0	0

Drugs targeting cohort genes (top 30)

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

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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
SCN9A	428	Binding:395, Functional:29, ADMET:3, Toxicity:1
SCN2A	203	Binding:172, Functional:20, ADMET:10, Toxicity:1
SCN1A	149	Binding:115, Functional:18, ADMET:14, Toxicity:2
HCN1	21	Binding:12, Functional:8, ADMET:1
SCN1B	15	Binding:7, ADMET:6, Toxicity:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ATP10A	7.6.2.1	P-type phospholipid transporter

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN1A	149
GABRG2	1,155
SCN2A	203
SCN9A	428

Pharmacogenomics

Cohort genes with a PharmGKB record: 10; 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, SCN9A
BEPRIDIL	4	SCN1A, SCN2A
DIBUCAINE	4	SCN1A, SCN2A
ARTICAINE	4	SCN1A, SCN2A
BUPIVACAINE	4	SCN1A, SCN2A
IMIPRAMINE	4	SCN1A, SCN2A, SCN9A
DROPERIDOL	4	SCN1A, SCN2A
DICYCLOMINE	4	SCN1A, SCN2A
TETRABENAZINE	4	SCN1A, SCN2A
PHENIRAMINE	4	SCN1A, SCN2A
PRILOCAINE	4	SCN1A, SCN2A
PROPOXYCAINE	4	SCN1A, SCN2A
PROPARACAINE	4	SCN1A, SCN2A
HEXYLCAINE	4	SCN1A, SCN2A
PRAMOXINE	4	SCN1A, SCN2A
BENOXINATE	4	SCN1A, SCN2A
QUINIDINE	4	SCN1A, SCN2A
FELODIPINE	4	SCN1A, SCN2A
PHENYTOIN	4	SCN1A, SCN2A
QUININE	4	SCN1A, SCN2A
NISOLDIPINE	4	SCN1A, SCN2A
NIFEDIPINE	4	SCN1A, SCN2A, SCN9A
PRAZOSIN	4	SCN1A, SCN2A
DILTIAZEM	4	SCN1A, SCN2A, SCN9A
PRENYLAMINE	4	SCN1A, SCN2A
COCAINE	4	SCN1A, SCN2A
TRIFLUOPERAZINE	4	SCN1A, SCN2A
CINNARIZINE	4	SCN1A, SCN2A
THIORIDAZINE	4	SCN1A, SCN2A
ETIDOCAINE	4	SCN1A, SCN2A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	4	SCN1A, GABRG2, SCN2A, SCN9A
B	Phased (≥1) drug, not yet approved	1	SCN1B
C	Druggable family + PDB, no drug	1	HCN1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	5	STX1B, SLC32A1, ATP10A, ANO4, SCN1A-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
STX1B	0	—
HCN1	21	—
SLC32A1	0	—
ATP10A	0	—
ANO4	0	—
SCN1A-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.