Autosomal dominant nocturnal frontal lobe epilepsy 5

Summary

Autosomal dominant nocturnal frontal lobe epilepsy 5 (MONDO:0014002) is a disease caused by KCNT1 (GenCC Strong), with 6 cohort genes.

At a glance

• Causal gene: KCNT1 (GenCC Strong)
• Cohort genes: 6
• ClinVar variants: 2,156

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant nocturnal frontal lobe epilepsy 5
Mondo ID	MONDO:0014002
OMIM	615005
DOID	DOID:0060686
UMLS	C3554306
MedGen	767220
GARD	0015891
Is cancer (heuristic)	no

Also known as: autosomal dominant nocturnal frontal lobe epilepsy caused by mutation in KCNT1 · autosomal dominant nocturnal frontal lobe epilepsy type 5 · ENFL5 · epilepsy nocturnal frontal lobe, 5 · epilepsy, nocturnal frontal lobe, 5 · epilepsy, nocturnal frontal lobe, type 5 · KCNT1 autosomal dominant nocturnal frontal lobe epilepsy

Data availability: 2,156 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › epilepsy › focal epilepsy › familial partial epilepsy › familial sleep-related hypermotor epilepsy › autosomal dominant nocturnal frontal lobe epilepsy 5

Related subtypes (4): autosomal dominant nocturnal frontal lobe epilepsy 1, autosomal dominant nocturnal frontal lobe epilepsy 2, autosomal dominant nocturnal frontal lobe epilepsy 3, autosomal dominant nocturnal frontal lobe epilepsy 4

Genetics & variants

GWAS landscape

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

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

317 likely benign, 224 uncertain significance, 30 conflicting classifications of pathogenicity, 12 benign/likely benign, 9 benign, 5 pathogenic, 2 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
126421	NM_020822.3(KCNT1):c.862G>A (p.Gly288Ser)	KCNT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1401332	NM_020822.3(KCNT1):c.2012C>T (p.Thr671Ile)	KCNT1	Pathogenic	criteria provided, single submitter
1457517	NM_020822.3(KCNT1):c.2687T>A (p.Met896Lys)	KCNT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1457519	NM_020822.3(KCNT1):c.2797C>G (p.Arg933Gly)	KCNT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1525584	NM_020822.3(KCNT1):c.2800G>T (p.Ala934Ser)	KCNT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
183028	NM_020822.3(KCNT1):c.2688G>A (p.Met896Ile)	KCNT1	Pathogenic	no assertion criteria provided
1486353	NM_020822.3(KCNT1):c.862G>T (p.Gly288Cys)	KCNT1	Likely pathogenic	criteria provided, single submitter
1503439	NM_020822.3(KCNT1):c.1309C>A (p.Leu437Ile)	KCNT1	Likely pathogenic	criteria provided, single submitter
1001305	NM_020822.3(KCNT1):c.1963G>A (p.Glu655Lys)	KCNT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1014642	NM_020822.3(KCNT1):c.3538G>A (p.Val1180Ile)	KCNT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1036350	NM_020822.3(KCNT1):c.2195C>T (p.Ser732Leu)	KCNT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1038198	NM_020822.3(KCNT1):c.3616C>T (p.His1206Tyr)	KCNT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1040246	NM_020822.3(KCNT1):c.1770G>A (p.Lys590=)	KCNT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1096238	NM_020822.3(KCNT1):c.2595-8G>A	KCNT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1132077	NM_020822.3(KCNT1):c.16G>A (p.Gly6Arg)	KCNT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
129352	NM_020822.3(KCNT1):c.1257C>G (p.Val419=)	KCNT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
129354	NM_020822.3(KCNT1):c.1879A>G (p.Ile627Val)	KCNT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
129355	NM_020822.3(KCNT1):c.2034C>T (p.Gly678=)	KCNT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
129360	NM_020822.3(KCNT1):c.2882G>A (p.Arg961His)	KCNT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1305092	NM_020822.3(KCNT1):c.41G>C (p.Cys14Ser)	KCNT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1310550	NM_020822.3(KCNT1):c.784C>T (p.Arg262Trp)	KCNT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1353315	NM_020822.3(KCNT1):c.3340C>G (p.Arg1114Gly)	KCNT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1401119	NM_020822.3(KCNT1):c.1984G>A (p.Val662Met)	KCNT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1401663	NM_020822.3(KCNT1):c.3409C>T (p.Arg1137Cys)	KCNT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1408450	NM_020822.3(KCNT1):c.4C>G (p.Pro2Ala)	KCNT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1418269	NM_020822.3(KCNT1):c.2050A>C (p.Thr684Pro)	KCNT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1423830	NM_020822.3(KCNT1):c.1328T>C (p.Met443Thr)	KCNT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1432042	NM_020822.3(KCNT1):c.518A>G (p.Lys173Arg)	KCNT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1439158	NM_020822.3(KCNT1):c.2482C>T (p.Arg828Cys)	KCNT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1444788	NM_020822.3(KCNT1):c.22C>G (p.Arg8Gly)	KCNT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 4 · 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
KCNT1	Strong	Autosomal dominant	autosomal dominant nocturnal frontal lobe epilepsy 5	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KCNT1	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
KCNT1	Orphanet:98784	Sleep-related hypermotor epilepsy
SPAG1	Orphanet:244	Primary ciliary dyskinesia
ABCA2	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KCNT1	HGNC:18865	ENSG00000107147	Q5JUK3	Potassium channel subfamily T member 1	gencc,clinvar
SPAG1	HGNC:11212	ENSG00000104450	Q07617	Sperm-associated antigen 1	clinvar
VAV2	HGNC:12658	ENSG00000160293	P52735	Guanine nucleotide exchange factor VAV2	clinvar
GPSM1	HGNC:17858	ENSG00000160360	Q86YR5	G-protein-signaling modulator 1	clinvar
TOR4A	HGNC:25981	ENSG00000198113	Q9NXH8	Torsin-4A	clinvar
ABCA2	HGNC:32	ENSG00000107331	Q9BZC7	ATP-binding cassette sub-family A member 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KCNT1	Potassium channel subfamily T member 1	Sodium-activated K(+) channel.
SPAG1	Sperm-associated antigen 1	May play a role in the cytoplasmic assembly of the ciliary dynein arms.
VAV2	Guanine nucleotide exchange factor VAV2	Guanine nucleotide exchange factor for the Rho family of Ras-related GTPases.
GPSM1	G-protein-signaling modulator 1	Guanine nucleotide dissociation inhibitor (GDI) which functions as a receptor-independent activator of heterotrimeric G-protein signaling.
ABCA2	ATP-binding cassette sub-family A member 2	Probable lipid transporter that modulates cholesterol sequestration in the late endosome/lysosome by regulating the intracellular sphingolipid metabolism, in turn participates in cholesterol homeostasis.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 3 · 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	1	18.6×	0.149
Transporter	1	13.0×	0.149
Scaffold/PPI	1	2.9×	0.401
Other/Unknown	3	0.9×	0.758

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KCNT1	Ion channel	yes		RCK_N, K_chnl_BK_asu, K_chnl_dom
SPAG1	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, RPAP3-like_C
VAV2	Scaffold/PPI	no		DH_dom, SH2, GDS_CDC24_CS
GPSM1	Other/Unknown	no		GoLoco_motif, TPR-like_helical_dom_sf, TPR_rpt
TOR4A	Other/Unknown	no		AAA+_ATPase, Torsin, P-loop_NTPase
ABCA2	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC2_TM

Expression context

Cohort genes with no expression data: 0.

6 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right hemisphere of cerebellum	3
cerebellar cortex	1
cerebellar hemisphere	1
bronchial epithelial cell	1
mucosa of sigmoid colon	1
palpebral conjunctiva	1
ganglionic eminence	1
parotid gland	1
ventricular zone	1
cardiac muscle of right atrium	1
tibia	1
buccal mucosa cell	1
granulocyte	1
mucosa of transverse colon	1
C1 segment of cervical spinal cord	1
spinal cord	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KCNT1	153	tissue_specific	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
SPAG1	249	ubiquitous	marker	bronchial epithelial cell, mucosa of sigmoid colon, palpebral conjunctiva
VAV2	248	ubiquitous	marker	parotid gland, ganglionic eminence, ventricular zone
GPSM1	235	ubiquitous	marker	tibia, cardiac muscle of right atrium, right hemisphere of cerebellum
TOR4A	184	ubiquitous	marker	buccal mucosa cell, mucosa of transverse colon, granulocyte
ABCA2	234	ubiquitous	marker	C1 segment of cervical spinal cord, spinal cord, right hemisphere of cerebellum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SPAG1	2,175
VAV2	1,746
ABCA2	1,678
KCNT1	1,562
GPSM1	1,472
TOR4A	437

Structural data

PDB: 3 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VAV2	P52735	7
KCNT1	Q5JUK3	6
SPAG1	Q07617	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TOR4A	Q9NXH8	79.35
ABCA2	Q9BZC7	71.46
GPSM1	Q86YR5	68.24

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 27. Enrichment computed across 6 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
ABC transporters in lipid homeostasis	1	150.3×	0.039	ABCA2
Signal transduction by L1	1	129.8×	0.039	VAV2
Azathioprine ADME	1	124.1×	0.039	VAV2
SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST)	1	124.1×	0.039	VAV2
VEGFR2 mediated vascular permeability	1	102.0×	0.039	VAV2
DAP12 signaling	1	92.1×	0.039	VAV2
FCERI mediated Ca+2 mobilization	1	89.2×	0.039	VAV2
FCERI mediated MAPK activation	1	86.5×	0.039	VAV2
GPVI-mediated activation cascade	1	77.2×	0.039	VAV2
EPH-ephrin mediated repulsion of cells	1	54.9×	0.043	VAV2
FCGR3A-mediated phagocytosis	1	46.8×	0.043	VAV2
NRAGE signals death through JNK	1	46.0×	0.043	VAV2
Regulation of actin dynamics for phagocytic cup formation	1	46.0×	0.043	VAV2
RHOB GTPase cycle	1	38.6×	0.043	VAV2
RHOG GTPase cycle	1	37.1×	0.043	VAV2
RHOC GTPase cycle	1	36.6×	0.043	VAV2
VEGFA-VEGFR2 Pathway	1	34.8×	0.043	VAV2
G alpha (12/13) signalling events	1	34.4×	0.043	VAV2
RAC2 GTPase cycle	1	31.7×	0.043	VAV2
ABC-family protein mediated transport	1	30.4×	0.043	ABCA2
RAC3 GTPase cycle	1	29.7×	0.043	VAV2
Platelet degranulation	1	22.0×	0.055	TOR4A
RHOA GTPase cycle	1	18.7×	0.061	VAV2
CDC42 GTPase cycle	1	18.1×	0.061	VAV2
RAC1 GTPase cycle	1	15.3×	0.069	VAV2
G alpha (i) signalling events	1	9.7×	0.103	GPSM1
Transport of small molecules	1	6.3×	0.150	ABCA2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of intracellular cholesterol transport	1	3370.4×	0.003	ABCA2
negative regulation of phospholipid biosynthetic process	1	3370.4×	0.003	ABCA2
negative regulation of sphingolipid biosynthetic process	1	3370.4×	0.003	ABCA2
regulation of protein localization to cell periphery	1	3370.4×	0.003	ABCA2
negative regulation of guanyl-nucleotide exchange factor activity	1	3370.4×	0.003	GPSM1
negative regulation of steroid metabolic process	1	1685.2×	0.004	ABCA2
ceramide translocation	1	1685.2×	0.004	ABCA2
regulation of post-translational protein modification	1	1685.2×	0.004	ABCA2
negative regulation of receptor-mediated endocytosis involved in cholesterol transport	1	1685.2×	0.004	ABCA2
positive regulation of low-density lipoprotein particle receptor catabolic process	1	1123.5×	0.005	ABCA2
ganglioside metabolic process	1	842.6×	0.006	ABCA2
regulation of intracellular cholesterol transport	1	842.6×	0.006	ABCA2
sphingomyelin metabolic process	1	674.1×	0.006	ABCA2
positive regulation of amyloid precursor protein biosynthetic process	1	674.1×	0.006	ABCA2
intracellular sphingolipid homeostasis	1	674.1×	0.006	ABCA2
negative regulation of cholesterol efflux	1	561.7×	0.006	ABCA2
glycosphingolipid metabolic process	1	481.5×	0.006	ABCA2
regulation of steroid metabolic process	1	481.5×	0.006	ABCA2
central nervous system myelin formation	1	481.5×	0.006	ABCA2
immune response-regulating cell surface receptor signaling pathway	1	374.5×	0.007	VAV2
response to cholesterol	1	337.0×	0.007	ABCA2
positive regulation of amyloid precursor protein catabolic process	1	337.0×	0.007	ABCA2
regulation of protein localization to cell surface	1	337.0×	0.007	ABCA2
negative regulation of GTPase activity	1	210.7×	0.010	GPSM1
sphingosine biosynthetic process	1	210.7×	0.010	ABCA2
axonemal dynein complex assembly	1	210.7×	0.010	SPAG1
positive regulation of amyloid-beta formation	1	177.4×	0.012	ABCA2
response to steroid hormone	1	168.5×	0.012	ABCA2
regulation of cell size	1	153.2×	0.013	VAV2
Fc-epsilon receptor signaling pathway	1	146.5×	0.013	VAV2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 6 evidence-associated genes (17%) 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
KCNT1	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNT1	2	4
SPAG1	0	0
VAV2	0	0
GPSM1	0	0
TOR4A	0	0
ABCA2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	KCNT1
QUINIDINE	4	KCNT1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
KCNT1	24	Binding:24

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

2 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
QUINIDINE	4	KCNT1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	KCNT1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	ABCA2
E	Difficult family or no structure, no drug	4	SPAG1, VAV2, GPSM1, TOR4A

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)
SPAG1	0	—
VAV2	0	—
GPSM1	0	—
TOR4A	0	—
ABCA2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.