Malignant migrating partial seizures of infancy

Summary

Malignant migrating partial seizures of infancy (MONDO:0017385) is a disease caused by KCNT1 (GenCC Definitive), with 9 cohort genes. The dominant Reactome pathway is Interaction between L1 and Ankyrins (3 cohort genes).

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: KCNT1 (GenCC Definitive)
• Cohort genes: 9
• ClinVar variants: 7
• Phenotypes (HPO): 25

Clinical features

Epidemiology

Prevalence records

4 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		114	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated
Point prevalence	1-9 / 1 000 000	0.11	United Kingdom	Validated
Prevalence at birth	1-9 / 1 000 000	0.4	United Kingdom	Validated

Signs & symptoms

Clinical features (HPO)

25 HPO clinical features (Orphanet curated; top 25 by frequency):

HPO ID	Term	Frequency
HP:0002376	Developmental regression	Very frequent (80-99%)
HP:0002540	Inability to walk	Very frequent (80-99%)
HP:0004302	Functional motor deficit	Very frequent (80-99%)
HP:0010841	Multifocal epileptiform discharges	Very frequent (80-99%)
HP:0012758	Neurodevelopmental delay	Very frequent (80-99%)
HP:0100543	Cognitive impairment	Very frequent (80-99%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0002059	Cerebral atrophy	Frequent (30-79%)
HP:0002069	Bilateral tonic-clonic seizure	Frequent (30-79%)
HP:0002384	Focal impaired awareness seizure	Frequent (30-79%)
HP:0006813	Focal hemiclonic seizure	Frequent (30-79%)
HP:0007334	Bilateral tonic-clonic seizure with focal onset	Frequent (30-79%)
HP:0010821	Focal emotional seizure with laughing	Frequent (30-79%)
HP:0032794	Myoclonic seizure	Frequent (30-79%)
HP:0000505	Visual impairment	Occasional (5-29%)
HP:0001273	Abnormal corpus callosum morphology	Occasional (5-29%)
HP:0001276	Hypertonia	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0002521	Hypsarrhythmia	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0011097	Epileptic spasm	Occasional (5-29%)
HP:0012448	Delayed myelination	Occasional (5-29%)
HP:0031834	Aortopulmonary collateral arteries	Occasional (5-29%)
HP:0000826	Precocious puberty	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	malignant migrating partial seizures of infancy
Mondo ID	MONDO:0017385
Orphanet	293181
ICD-11	1727727812
NCIT	C125387
SNOMED CT	733195008, 784345005
UMLS	C4518639
MedGen	1381392
GARD	0012919, 0026016
Is cancer (heuristic)	no

Also known as: EIMFS · epilepsy of infancy with migrating focal seizures · malignant migrating partial epilepsy of infancy · malignant migrating Partial seizures in infancy · migrating partial epilepsy of infancy · migrating Partial seizures in infancy · migrating partial seizures of infancy · MMPEI · MMPSI · MPEI · MPSI

Data availability: 7 ClinVar variants · 10 GenCC gene-disease records.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › epilepsy › epilepsy syndrome › neonatal epilepsy syndrome › malignant migrating partial seizures of infancy

Related subtypes (5): severe neonatal-onset encephalopathy with microcephaly, developmental and epileptic encephalopathy, 39, benign neonatal seizures, undetermined early-onset epileptic encephalopathy, benign idiopathic neonatal seizures

Subtypes (3): developmental and epileptic encephalopathy, 12, developmental and epileptic encephalopathy, 16, developmental and epileptic encephalopathy, 34

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

7 retrieved; paginated sample, class counts are floors:

3 pathogenic/likely pathogenic, 2 uncertain significance, 1 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
280499	NM_020822.3(KCNT1):c.1546A>G (p.Met516Val)	KCNT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
575241	NM_020822.3(KCNT1):c.2896G>A (p.Ala966Thr)	KCNT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
375505	NM_001040142.2(SCN2A):c.3967A>G (p.Met1323Val)	SCN2A	Pathogenic	criteria provided, multiple submitters, no conflicts
801776	NM_001040142.2(SCN2A):c.638T>C (p.Val213Ala)	SCN2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
375526	NM_020822.3(KCNT1):c.2839A>G (p.Lys947Glu)	KCNT1	Likely pathogenic	criteria provided, single submitter
2935475	NM_020822.3(KCNT1):c.773G>A (p.Arg258His)	KCNT1	Uncertain significance	criteria provided, single submitter
2584794	NM_001199107.2(TBC1D24):c.571T>C (p.Cys191Arg)	TBC1D24	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 109 · Orphanet: 41 · 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
KCNQ2	Definitive	Autosomal dominant	seizures, benign familial neonatal, 1	12
KCNT1	Definitive	Autosomal dominant	malignant migrating partial seizures of infancy	10
PIGA	Definitive	X-linked	multiple congenital anomalies-hypotonia-seizures syndrome 2	9
SCN1A	Definitive	Autosomal dominant	generalized epilepsy with febrile seizures plus, type 2	20
SCN2A	Strong	Autosomal dominant	seizures, benign familial infantile, 3	16
SLC12A5	Strong	Autosomal recessive	epilepsy of infancy with migrating focal seizures	9
PLCB1	Supportive	Autosomal dominant	malignant migrating partial seizures of infancy	6
SLC25A22	Supportive	Autosomal dominant	malignant migrating partial seizures of infancy	6
TBC1D24	Supportive	Autosomal dominant	malignant migrating partial seizures of infancy	21

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SCN2A	Orphanet:140927	Self-limited neonatal-infantile epilepsy
SCN2A	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
SCN2A	Orphanet:2131	Alternating hemiplegia of childhood
SCN2A	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
SCN2A	Orphanet:306	Self-limited infantile epilepsy
SCN2A	Orphanet:33069	Dravet syndrome
SCN2A	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN2A	Orphanet:697160	Infantile epileptic spasms syndrome
KCNT1	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
KCNT1	Orphanet:98784	Sleep-related hypermotor epilepsy
TBC1D24	Orphanet:163727	Rolandic epilepsy-paroxysmal exercise-induced dystonia-writer’s cramp syndrome
TBC1D24	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
TBC1D24	Orphanet:352582	Familial infantile myoclonic epilepsy
TBC1D24	Orphanet:352587	Focal epilepsy-intellectual disability-cerebro-cerebellar malformation
TBC1D24	Orphanet:352596	Progressive myoclonic epilepsy with dystonia
TBC1D24	Orphanet:79500	DOORS syndrome
TBC1D24	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
TBC1D24	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
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
SLC12A5	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
PLCB1	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
PLCB1	Orphanet:697160	Infantile epileptic spasms syndrome
SLC25A22	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
SLC25A22	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
KCNQ2	Orphanet:140927	Self-limited neonatal-infantile epilepsy
KCNQ2	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
KCNQ2	Orphanet:1949	Self-limited neonatal epilepsy
KCNQ2	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
KCNQ2	Orphanet:306	Self-limited infantile epilepsy
KCNQ2	Orphanet:439218	KCNQ2-related developmental and epileptic encephalopathy
PIGA	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
PIGA	Orphanet:300496	Multiple congenital anomalies-hypotonia-seizures syndrome type 2
PIGA	Orphanet:397922	Ferro-cerebro-cutaneous syndrome
PIGA	Orphanet:447	Paroxysmal nocturnal hemoglobinuria
PIGA	Orphanet:697160	Infantile epileptic spasms syndrome

Cohort genes → proteins

9 cohort genes, 9 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	9

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCN2A	HGNC:10588	ENSG00000136531	Q99250	Sodium channel protein type 2 subunit alpha	gencc,clinvar
KCNT1	HGNC:18865	ENSG00000107147	Q5JUK3	Potassium channel subfamily T member 1	gencc,clinvar
TBC1D24	HGNC:29203	ENSG00000162065	Q9ULP9	TBC1 domain family member 24	gencc,clinvar
SCN1A	HGNC:10585	ENSG00000144285	P35498	Sodium channel protein type 1 subunit alpha	gencc
SLC12A5	HGNC:13818	ENSG00000124140	Q9H2X9	Solute carrier family 12 member 5	gencc
PLCB1	HGNC:15917	ENSG00000182621	Q9NQ66	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1	gencc
SLC25A22	HGNC:19954	ENSG00000177542	Q9H936	Mitochondrial glutamate carrier 1	gencc
KCNQ2	HGNC:6296	ENSG00000075043	O43526	Potassium voltage-gated channel subfamily KQT member 2	gencc
PIGA	HGNC:8957	ENSG00000165195	P37287	Phosphatidylinositol N-acetylglucosaminyltransferase subunit A	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCN2A	Sodium channel protein type 2 subunit alpha	Mediates the voltage-dependent sodium ion permeability of excitable membranes.
KCNT1	Potassium channel subfamily T member 1	Sodium-activated K(+) channel.
TBC1D24	TBC1 domain family member 24	May act as a GTPase-activating protein for Rab family protein(s).
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.
SLC12A5	Solute carrier family 12 member 5	Mediates electroneutral potassium-chloride cotransport in mature neurons and is required for neuronal Cl(-) homeostasis.
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.
SLC25A22	Mitochondrial glutamate carrier 1	Mitochondrial glutamate/H(+) symporter.
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.
PIGA	Phosphatidylinositol N-acetylglucosaminyltransferase subunit A	Catalytic subunit of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex that catalyzes the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine to phosphatidylinositol and participates in the first s…

Protein-family classification

Druggable: 6 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.67

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	49.6×	3e-06
Transporter	1	8.6×	0.220
Enzyme (other)	1	1.3×	0.724
Other/Unknown	3	0.6×	0.955

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCN2A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
KCNT1	Ion channel	yes		RCK_N, K_chnl_BK_asu, K_chnl_dom
TBC1D24	Other/Unknown	no		Rab-GAP-TBC_dom, TLDc_dom, Rab-GAP_TBC_sf
SCN1A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a1su
SLC12A5	Other/Unknown	no		KCL_cotranspt, AA-permease/SLC12A_dom, SLC12A_fam
PLCB1	Enzyme (other)	yes	3.1.4.11	C2_dom, PLipase_C_PInositol-sp_X_dom, PI-PLC_fam
SLC25A22	Transporter	yes		MCP, MCP_transmembrane, MCP_dom_sf
KCNQ2	Ion channel	yes		K_chnl_volt-dep_KCNQ, K_chnl_volt-dep_KCNQ2, Ion_trans_dom
PIGA	Other/Unknown	no		Glyco_trans_1, PIGA_GPI_anchor_biosynthesis, PIG-A/GPI3

Expression context

Cohort genes with no expression data: 0.

9 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)	9
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	4
cerebellar cortex	4
cerebellar hemisphere	4
right hemisphere of cerebellum	4
middle temporal gyrus	2
cerebellar vermis	1
parotid gland	1
lateral nuclear group of thalamus	1
primary visual cortex	1
endothelial cell	1
superior frontal gyrus	1
endometrium epithelium	1
mucosa of stomach	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCN2A	187	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, cerebellar vermis
KCNT1	153	tissue_specific	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
TBC1D24	227	ubiquitous	marker	parotid gland, Brodmann (1909) area 23, middle temporal gyrus
SCN1A	154	tissue_specific	marker	Brodmann (1909) area 23, lateral nuclear group of thalamus, primary visual cortex
SLC12A5	205	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
PLCB1	278	ubiquitous	marker	endothelial cell, Brodmann (1909) area 23, superior frontal gyrus
SLC25A22	228	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
KCNQ2	183	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
PIGA	266	ubiquitous	marker	secondary oocyte, mucosa of stomach, endometrium epithelium

Protein interactions among cohort

Intra-cohort edges: 15.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KCNQ2	3,388
SCN2A	2,810
PIGA	2,324
SCN1A	2,287
SLC12A5	2,287
PLCB1	2,235
KCNT1	1,562
SLC25A22	1,483
TBC1D24	1,016

Intra-cohort edges

A	B	Sources
KCNQ2	KCNT1	string_interaction
KCNQ2	SCN1A	string_interaction
KCNQ2	SCN2A	string_interaction
KCNQ2	SLC25A22	string_interaction
KCNT1	SCN1A	string_interaction
KCNT1	SCN2A	string_interaction
KCNT1	SLC25A22	string_interaction
KCNT1	TBC1D24	string_interaction
PLCB1	SLC25A22	string_interaction
SCN1A	SCN2A	biogrid_interaction, string_interaction
SCN1A	SLC25A22	string_interaction
SCN1A	TBC1D24	string_interaction
SCN2A	SLC25A22	string_interaction
SCN2A	TBC1D24	string_interaction
SLC25A22	TBC1D24	string_interaction

Structural data

PDB: 5 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KCNQ2	O43526	39
KCNT1	Q5JUK3	6
SCN2A	Q99250	5
SLC12A5	Q9H2X9	2
SCN1A	P35498	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PIGA	P37287	86.22
PLCB1	Q9NQ66	84.55
TBC1D24	Q9ULP9	84.46
SLC25A22	Q9H936	78.48

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 33. Enrichment computed across 9 evidence-associated genes (8 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 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interaction between L1 and Ankyrins	3	138.2×	3e-05	SCN2A, SCN1A, KCNQ2
L1CAM interactions	3	45.1×	5e-04	SCN2A, SCN1A, KCNQ2
Phase 0 - rapid depolarisation	2	86.5×	0.002	SCN2A, SCN1A
Axon guidance	3	16.9×	0.004	SCN2A, SCN1A, KCNQ2
Nervous system development	3	16.1×	0.004	SCN2A, SCN1A, KCNQ2
Cardiac conduction	2	27.2×	0.012	SCN2A, SCN1A
Cation-coupled Chloride cotransporters	1	203.9×	0.020	SLC12A5
Muscle contraction	2	19.3×	0.020	SCN2A, SCN1A
Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion	1	178.4×	0.021	PLCB1
Malate-aspartate shuttle	1	158.6×	0.021	SLC25A22
Acetylcholine regulates insulin secretion	1	142.8×	0.021	PLCB1
Synthesis of glycosylphosphatidylinositol (GPI)	1	79.3×	0.032	PIGA
G beta:gamma signalling through PLC beta	1	71.4×	0.032	PLCB1
Presynaptic function of Kainate receptors	1	68.0×	0.032	PLCB1
Developmental Biology	3	5.4×	0.032	SCN2A, SCN1A, KCNQ2
Synthesis of IP3 and IP4 in the cytosol	1	52.9×	0.038	PLCB1
SLC-mediated transport of neurotransmitters	1	51.0×	0.038	SLC25A22
Rab regulation of trafficking	1	46.0×	0.039	TBC1D24
Sensory perception of taste	1	42.0×	0.041	SCN2A
Sensory perception of sweet, bitter, and umami (glutamate) taste	1	34.8×	0.046	SCN2A
PLC beta mediated events	1	33.2×	0.046	PLCB1
TBC/RABGAPs	1	32.4×	0.046	TBC1D24
Voltage gated Potassium channels	1	30.4×	0.047	KCNQ2
Ca2+ pathway	1	22.3×	0.060	PLCB1
Potassium Channels	1	16.8×	0.076	KCNQ2
R-HSA-425393	1	16.2×	0.076	SLC12A5
Sensory Perception	1	11.9×	0.099	SCN2A
SLC-mediated transmembrane transport	1	7.4×	0.149	SLC12A5
G alpha (q) signalling events	1	7.2×	0.149	PLCB1
Neuronal System	1	5.5×	0.184	KCNQ2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 9 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	2	156.0×	0.006	SCN2A, SCN1A
neuronal action potential	2	107.0×	0.007	SCN2A, SCN1A
cellular response to glyceraldehyde	1	1872.4×	0.007	PLCB1
negative regulation of monocyte extravasation	1	1872.4×	0.007	PLCB1
hypotonic response	1	936.2×	0.007	SLC12A5
intrinsic apoptotic signaling pathway in response to osmotic stress	1	936.2×	0.007	SCN2A
phosphatidylinositol catabolic process	1	936.2×	0.007	PLCB1
thermosensory behavior	1	936.2×	0.007	SLC12A5
activation of meiosis involved in egg activation	1	936.2×	0.007	PLCB1
cellular response to fluoride	1	936.2×	0.007	PLCB1
learning	2	62.4×	0.007	SLC12A5, PLCB1
sodium ion transport	2	60.4×	0.007	SCN2A, SCN1A
sodium ion transmembrane transport	2	45.1×	0.007	SCN2A, SCN1A
memory	2	40.7×	0.007	SCN2A, PLCB1
monoatomic ion transport	2	34.7×	0.009	SLC12A5, SLC25A22
regulation of retrograde trans-synaptic signaling by endocanabinoid	1	624.1×	0.009	PLCB1
inositol trisphosphate metabolic process	1	468.1×	0.010	PLCB1
positive regulation of developmental growth	1	468.1×	0.010	PLCB1
negative regulation of cellular response to oxidative stress	1	468.1×	0.010	TBC1D24
potassium ion transmembrane transport	2	30.2×	0.010	KCNT1, KCNQ2
regulation of fertilization	1	312.1×	0.014	PLCB1
cellular response to ionomycin	1	312.1×	0.014	PLCB1
phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathway	1	234.1×	0.015	PLCB1
positive regulation of glycoprotein biosynthetic process	1	234.1×	0.015	PLCB1
postsynaptic neurotransmitter receptor diffusion trapping	1	234.1×	0.015	SLC12A5
cellular response to vasopressin	1	234.1×	0.015	PLCB1
interleukin-12-mediated signaling pathway	1	208.1×	0.015	PLCB1
malate-aspartate shuttle	1	208.1×	0.015	SLC25A22
regulation of establishment of endothelial barrier	1	208.1×	0.015	PLCB1
ligand-gated ion channel signaling pathway	1	208.1×	0.015	PLCB1

Therapeutics

Drug target analysis

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

Druggability breadth: 6 of 9 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

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

Symbol	Example approved molecule
SCN2A	BEPRIDIL
KCNT1	BEPRIDIL
SCN1A	MEXILETINE HYDROCHLORIDE
KCNQ2	FLUPIRTINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN2A	99	4
SCN1A	94	4
KCNQ2	4	4
KCNT1	2	4
TBC1D24	0	0
SLC12A5	0	0
PLCB1	0	0
SLC25A22	0	0
PIGA	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	KCNT1, SCN1A, SCN2A
DIBUCAINE	4	SCN1A, SCN2A
ARTICAINE	4	SCN1A, SCN2A
BUPIVACAINE	4	SCN1A, SCN2A
IMIPRAMINE	4	SCN1A, SCN2A
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	KCNT1, SCN1A, SCN2A
FELODIPINE	4	SCN1A, SCN2A
PHENYTOIN	4	SCN1A, SCN2A
QUININE	4	SCN1A, SCN2A
NISOLDIPINE	4	SCN1A, SCN2A
NIFEDIPINE	4	SCN1A, SCN2A
PRAZOSIN	4	SCN1A, SCN2A
DILTIAZEM	4	SCN1A, SCN2A
PRENYLAMINE	4	SCN1A, SCN2A
COCAINE	4	SCN1A, SCN2A
TRIFLUOPERAZINE	4	SCN1A, SCN2A
CINNARIZINE	4	SCN1A, SCN2A
THIORIDAZINE	4	SCN1A, SCN2A
ETIDOCAINE	4	SCN1A, SCN2A
CHLORPHENIRAMINE	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
SCN2A	203	Binding:172, Functional:20, ADMET:10, Toxicity:1
SCN1A	149	Binding:115, Functional:18, ADMET:14, Toxicity:2
KCNQ2	145	Binding:136, Functional:7, ADMET:1, Toxicity:1
KCNT1	24	Binding:24
PLCB1	11	Binding:9, Functional:2
SLC12A5	6	Functional:4, Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PLCB1	3.1.4.11	phosphoinositide phospholipase C

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN2A	203
SCN1A	149
KCNQ2	145

Pharmacogenomics

Cohort genes with a PharmGKB record: 9; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
BEPRIDIL	4	KCNT1, SCN1A, SCN2A
DIBUCAINE	4	SCN1A, SCN2A
ARTICAINE	4	SCN1A, SCN2A
BUPIVACAINE	4	SCN1A, SCN2A
IMIPRAMINE	4	SCN1A, SCN2A
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	KCNT1, SCN1A, SCN2A
FELODIPINE	4	SCN1A, SCN2A
PHENYTOIN	4	SCN1A, SCN2A
QUININE	4	SCN1A, SCN2A
NISOLDIPINE	4	SCN1A, SCN2A
NIFEDIPINE	4	SCN1A, SCN2A
PRAZOSIN	4	SCN1A, SCN2A
DILTIAZEM	4	SCN1A, SCN2A
PRENYLAMINE	4	SCN1A, SCN2A
COCAINE	4	SCN1A, SCN2A
TRIFLUOPERAZINE	4	SCN1A, SCN2A
CINNARIZINE	4	SCN1A, SCN2A
THIORIDAZINE	4	SCN1A, SCN2A
ETIDOCAINE	4	SCN1A, SCN2A
CHLORPHENIRAMINE	4	SCN1A, SCN2A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	4	SCN2A, KCNT1, SCN1A, KCNQ2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	2	PLCB1, SLC25A22
E	Difficult family or no structure, no drug	3	TBC1D24, SLC12A5, PIGA

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TBC1D24	0	KCNT1
SLC12A5	6	—
PLCB1	11	—
SLC25A22	0	—
PIGA	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.