Febrile seizures, familial, 2

Summary

Febrile seizures, familial, 2 (MONDO:0011231) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 9

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	febrile seizures, familial, 2
Mondo ID	MONDO:0011231
MeSH	C566541
DOID	DOID:0111310
UMLS	C1865342
MedGen	355446
Is cancer (heuristic)	no

Also known as: FEB2 · febrile seizures, familial, 2 · generalised epilepsy with febrile seizures plus, type 11 · generalized epilepsy with febrile seizures plus, type 11

Data availability: 9 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › febrile seizures, familial › febrile seizures, familial, 2

Related subtypes (12): febrile seizures, familial, 1, febrile seizures, familial, 4, generalized epilepsy with febrile seizures plus, type 2, febrile seizures, familial, 8, febrile seizures, familial, 6, febrile seizures, familial, 5, febrile seizures, familial, 7, familial febrile seizures 9, febrile seizures, familial, 10, febrile seizures, familial, 11, febrile seizures, familial, 3a, febrile seizures, familial, 3b

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

9 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 3 risk factor, 1 pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1240010	NM_001194.4(HCN2):c.377C>T (p.Ser126Leu)	HCN2	Pathogenic	no assertion criteria provided
1240011	NM_001194.4(HCN2):c.1895C>G (p.Ser632Trp)	HCN2	risk factor	no assertion criteria provided
1240012	NM_001194.4(HCN2):c.736G>A (p.Val246Met)	HCN2	risk factor	no assertion criteria provided
1240013	NM_001194.4(HCN2):c.1543G>A (p.Glu515Lys)	HCN2	risk factor	no assertion criteria provided
2431846	NM_001194.4(HCN2):c.1682A>G (p.Lys561Arg)	HCN2	Uncertain significance	criteria provided, single submitter
2576595	NM_001194.4(HCN2):c.1641del (p.Asn547fs)	HCN2	Uncertain significance	criteria provided, single submitter
2578550	NM_001194.4(HCN2):c.443A>T (p.Glu148Val)	HCN2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2671658	NM_001194.4(HCN2):c.1657G>A (p.Val553Ile)	HCN2	Uncertain significance	criteria provided, single submitter
252561	NM_001194.4(HCN2):c.2144CGC[4] (p.Pro719_Pro721del)	HCN2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 0 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

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
HCN2	HGNC:4846	ENSG00000099822	Q9UL51	Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HCN2	Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2	Hyperpolarization-activated ion channel that is permeable to sodium and potassium ions.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Ion channel	1	111.5×	0.009

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HCN2	Ion channel	yes		cNMP-bd_dom, K_chnl_volt-dep_EAG/ELK/ERG, Ion_trans_dom

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
C1 segment of cervical spinal cord	1
putamen	1
right frontal lobe	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HCN2	177	broad	yes	C1 segment of cervical spinal cord, right frontal lobe, putamen

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HCN2	1,103

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HCN2	Q9UL51	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
HCN channels	1	2855.0×	4e-04	HCN2

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
cellular response to aldosterone	1	2407.4×	0.002	HCN2
cellular response to cGMP	1	2106.5×	0.002	HCN2
regulation of membrane depolarization	1	1872.4×	0.002	HCN2
ammonium transmembrane transport	1	1872.4×	0.002	HCN2
membrane depolarization during cardiac muscle cell action potential	1	1404.3×	0.002	HCN2
sodium ion import across plasma membrane	1	624.1×	0.003	HCN2
potassium ion import across plasma membrane	1	366.4×	0.005	HCN2
cellular response to cAMP	1	290.6×	0.006	HCN2
regulation of membrane potential	1	230.8×	0.006	HCN2
sodium ion transmembrane transport	1	203.0×	0.006	HCN2
potassium ion transmembrane transport	1	135.9×	0.009	HCN2
cell-cell signaling	1	69.6×	0.014	HCN2
response to xenobiotic stimulus	1	69.1×	0.014	HCN2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HCN2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
HCN2	12	Binding:6, Functional:4, ADMET:2

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

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	HCN2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HCN2	12	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.