Autosomal dominant nocturnal frontal lobe epilepsy 4

Summary

Autosomal dominant nocturnal frontal lobe epilepsy 4 (MONDO:0012474) is a disease caused by CHRNA2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: CHRNA2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 139

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant nocturnal frontal lobe epilepsy 4
Mondo ID	MONDO:0012474
MeSH	C563679
OMIM	610353
DOID	DOID:0060685, DOID:0081119
UMLS	C1835905
MedGen	332082
GARD	0015481
Is cancer (heuristic)	no

Also known as: autosomal dominant nocturnal frontal lobe epilepsy caused by mutation in CHRNA2 · autosomal dominant nocturnal frontal lobe epilepsy type 4 · CHRNA2 autosomal dominant nocturnal frontal lobe epilepsy · ENFL4 · epilepsy, nocturnal frontal lobe, 4 · epilepsy, nocturnal frontal lobe, type 4

Data availability: 139 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 4

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 5

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

139 retrieved; paginated sample, class counts are floors:

60 uncertain significance, 37 benign, 30 conflicting classifications of pathogenicity, 8 benign/likely benign, 2 pathogenic, 1 likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
17504	NM_000742.4(CHRNA2):c.836T>A (p.Ile279Asn)	CHRNA2	Pathogenic	no assertion criteria provided
522582	NM_000742.4(CHRNA2):c.889A>T (p.Ile297Phe)	CHRNA2	Pathogenic	no assertion criteria provided
4277698	NM_000742.4(CHRNA2):c.487G>A (p.Ala163Thr)	CHRNA2	Likely pathogenic	criteria provided, single submitter
128736	NM_000742.4(CHRNA2):c.1234G>A (p.Glu412Lys)	CHRNA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
136753	NM_000742.4(CHRNA2):c.1434C>A (p.Asp478Glu)	CHRNA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
197689	NM_000742.4(CHRNA2):c.383G>A (p.Gly128Asp)	CHRNA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
204946	NM_000742.4(CHRNA2):c.745G>A (p.Ala249Thr)	CHRNA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
204952	NM_000742.4(CHRNA2):c.173C>T (p.Thr58Ile)	CHRNA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
204959	NM_000742.4(CHRNA2):c.503C>T (p.Thr168Met)	CHRNA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
204968	NM_000742.4(CHRNA2):c.1073G>T (p.Ser358Ile)	CHRNA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
204970	NM_000742.4(CHRNA2):c.1123C>G (p.Pro375Ala)	CHRNA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
204979	NM_000742.4(CHRNA2):c.140C>T (p.Thr47Met)	CHRNA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
204982	NM_000742.4(CHRNA2):c.202C>T (p.Arg68Trp)	CHRNA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
204993	NM_000742.4(CHRNA2):c.215G>C (p.Arg72Pro)	CHRNA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2688780	NM_000742.4(CHRNA2):c.51G>T (p.Trp17Cys)	CHRNA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
282149	NM_000742.4(CHRNA2):c.937C>T (p.Leu313Phe)	CHRNA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
289277	NM_000742.4(CHRNA2):c.166A>T (p.Thr56Ser)	CHRNA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
362693	NM_000742.4(CHRNA2):c.1530C>T (p.Ile510=)	CHRNA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
362695	NM_000742.4(CHRNA2):c.1099C>T (p.Arg367Trp)	CHRNA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
362696	NM_000742.4(CHRNA2):c.339+10C>A	CHRNA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
362698	NM_000742.4(CHRNA2):c.203G>C (p.Arg68Pro)	CHRNA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
362717	NM_000742.4(CHRNA2):c.-565T>A	CHRNA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
392001	NM_000742.4(CHRNA2):c.869C>T (p.Pro290Leu)	CHRNA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
545945	NM_000742.4(CHRNA2):c.1393del (p.His465fs)	CHRNA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
587981	NM_000742.4(CHRNA2):c.1105dup (p.Ala369fs)	CHRNA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
625918	NM_000742.4(CHRNA2):c.1418T>G (p.Val473Gly)	CHRNA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
857708	NM_000742.4(CHRNA2):c.1465-3C>T	CHRNA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
909008	NM_000742.4(CHRNA2):c.1103G>T (p.Gly368Val)	CHRNA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
909010	NM_000742.4(CHRNA2):c.957G>A (p.Pro319=)	CHRNA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
909874	NM_000742.4(CHRNA2):c.430G>A (p.Asp144Asn)	CHRNA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
CHRNA2	Strong	Autosomal dominant	autosomal dominant nocturnal frontal lobe epilepsy 4	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CHRNA2	Orphanet:98784	Sleep-related hypermotor epilepsy

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CHRNA2	HGNC:1956	ENSG00000120903	Q15822	Neuronal acetylcholine receptor subunit alpha-2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CHRNA2	Neuronal acetylcholine receptor subunit alpha-2	Component of neuronal acetylcholine receptors (nAChRs) that function as pentameric, ligand-gated cation channels with high calcium permeability among other activities. nAChRs are excitatory neurotrasnmitter receptors formed by a collection…

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CHRNA2	Other/Unknown	no		Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cervix squamous epithelium	1
gingival epithelium	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CHRNA2	143	tissue_specific	yes	cervix squamous epithelium, primordial germ cell in gonad, gingival epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CHRNA2	982

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CHRNA2	Q15822	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Highly calcium permeable nicotinic acetylcholine receptors	1	1268.9×	0.002	CHRNA2
Highly calcium permeable postsynaptic nicotinic acetylcholine receptors	1	1038.2×	0.002	CHRNA2
Presynaptic nicotinic acetylcholine receptors	1	951.7×	0.002	CHRNA2
Acetylcholine binding and downstream events	1	815.7×	0.002	CHRNA2
Postsynaptic nicotinic acetylcholine receptors	1	815.7×	0.002	CHRNA2
Neurotransmitter receptors and postsynaptic signal transmission	1	100.2×	0.013	CHRNA2
Transmission across Chemical Synapses	1	76.1×	0.015	CHRNA2
Neuronal System	1	44.3×	0.023	CHRNA2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
modulation of inhibitory postsynaptic potential	1	16852.0×	7e-04	CHRNA2
cellular response to nicotine	1	2106.5×	0.003	CHRNA2
synaptic transmission, cholinergic	1	802.5×	0.004	CHRNA2
acetylcholine receptor signaling pathway	1	624.1×	0.004	CHRNA2
neuromuscular synaptic transmission	1	601.9×	0.004	CHRNA2
membrane depolarization	1	510.7×	0.004	CHRNA2
presynaptic modulation of chemical synaptic transmission	1	455.5×	0.004	CHRNA2
response to nicotine	1	421.3×	0.004	CHRNA2
regulation of synaptic plasticity	1	259.3×	0.005	CHRNA2
monoatomic ion transmembrane transport	1	208.1×	0.006	CHRNA2
monoatomic ion transport	1	156.0×	0.007	CHRNA2
signal transduction	1	16.1×	0.062	CHRNA2

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
CHRNA2	VARENICLINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CHRNA2	4	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VARENICLINE	4	CHRNA2
MECAMYLAMINE	4	CHRNA2
NICOTINE	4	CHRNA2
ALTINICLINE	2	CHRNA2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CHRNA2	40	Binding:37, Functional:2, ADMET:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

4 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)
VARENICLINE	4	CHRNA2
MECAMYLAMINE	4	CHRNA2
NICOTINE	4	CHRNA2
ALTINICLINE	2	CHRNA2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CHRNA2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.