Epilepsy, familial focal, with variable foci 2

Summary

Epilepsy, familial focal, with variable foci 2 (MONDO:0014924) is a disease caused by NPRL2 (GenCC Strong), with 4 cohort genes.

At a glance

• Causal gene: NPRL2 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 48

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	epilepsy, familial focal, with variable foci 2
Mondo ID	MONDO:0014924
OMIM	617116
DOID	DOID:0081422
UMLS	C4310709
MedGen	934676
GARD	0018203
Is cancer (heuristic)	no

Also known as: epilepsy, familial focal, with variable foci 2 · epilepsy, familial focal, with variable foci 2; FFEVF2 · epilepsy, familial focal, with variable foci caused by mutation in NPRL2 · epilepsy, familial focal, with variable foci type 2 · FFEVF2 · NPRL2 epilepsy, familial focal, with variable foci

Data availability: 48 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 focal epilepsy with variable foci › epilepsy, familial focal, with variable foci 2

Related subtypes (3): epilepsy, familial focal, with variable foci 3, epilepsy, familial focal, with variable foci 1, epilepsy, familial focal, with variable foci 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

48 retrieved; paginated sample, class counts are floors:

25 uncertain significance, 8 likely pathogenic, 6 pathogenic, 5 conflicting classifications of pathogenicity, 3 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
800932	NM_003995.4(NPR2):c.2966G>A (p.Arg989Gln)	NPR2	Pathogenic	criteria provided, single submitter
1526377	NM_006545.5(NPRL2):c.57_58delinsC (p.Gly20fs)	NPRL2	Pathogenic	criteria provided, multiple submitters, no conflicts
254363	NM_006545.5(NPRL2):c.883C>T (p.Arg295Ter)	NPRL2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
254364	NM_006545.5(NPRL2):c.314T>C (p.Leu105Pro)	NPRL2	Pathogenic	no assertion criteria provided
254365	NM_006545.5(NPRL2):c.68_69del (p.Ile23fs)	NPRL2	Pathogenic	no assertion criteria provided
4291119	NM_006545.5(NPRL2):c.941_948dup (p.Gly317fs)	NPRL2	Pathogenic	criteria provided, single submitter
4531904	NM_006545.5(NPRL2):c.754C>T (p.Gln252Ter)	NPRL2	Pathogenic	criteria provided, single submitter
986339	NM_006545.5(NPRL2):c.932+1G>A	NPRL2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
418389	NM_003995.4(NPR2):c.2966G>T (p.Arg989Leu)	SPAG8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
800931	NM_003995.4(NPR2):c.1032T>G (p.Tyr344Ter)	NPR2	Likely pathogenic	no assertion criteria provided
1297009	NM_006545.5(NPRL2):c.865_871del (p.Ser289fs)	NPRL2	Likely pathogenic	criteria provided, single submitter
1696508	NM_006545.5(NPRL2):c.562C>T (p.Gln188Ter)	NPRL2	Likely pathogenic	criteria provided, single submitter
3068298	NM_006545.5(NPRL2):c.233G>A (p.Arg78His)	NPRL2	Likely pathogenic	criteria provided, single submitter
4531903	NM_006545.5(NPRL2):c.814+2T>C	NPRL2	Likely pathogenic	criteria provided, single submitter
4685551	NM_006545.5(NPRL2):c.52_53del (p.Thr18fs)	NPRL2	Likely pathogenic	criteria provided, single submitter
692035	NM_006545.5(NPRL2):c.445_448+3del	NPRL2	Likely pathogenic	criteria provided, single submitter
931493	NM_006545.5(NPRL2):c.491dup (p.Asp165fs)	NPRL2	Likely pathogenic	criteria provided, single submitter
1342320	NM_006545.5(NPRL2):c.694G>A (p.Val232Ile)	NPRL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1804017	NM_006545.5(NPRL2):c.232C>T (p.Arg78Cys)	NPRL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2434429	NM_006545.5(NPRL2):c.728A>G (p.Asn243Ser)	NPRL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
254362	NM_006545.5(NPRL2):c.100C>T (p.Arg34Ter)	NPRL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1684544	NM_003995.4(NPR2):c.2794C>T (p.Arg932Cys)	SPAG8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2671799	NM_004366.6(CLCN2):c.2270C>T (p.Ala757Val)	CLCN2	Uncertain significance	criteria provided, single submitter
1199190	NM_006545.5(NPRL2):c.472A>G (p.Lys158Glu)	NPRL2	Uncertain significance	criteria provided, single submitter
1251968	NM_006545.5(NPRL2):c.661C>T (p.Arg221Cys)	NPRL2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1325804	NM_006545.5(NPRL2):c.586-3C>A	NPRL2	Uncertain significance	criteria provided, single submitter
1697305	NM_006545.5(NPRL2):c.683T>C (p.Leu228Pro)	NPRL2	Uncertain significance	criteria provided, single submitter
1698765	NM_006545.5(NPRL2):c.1004G>A (p.Arg335Gln)	NPRL2	Uncertain significance	criteria provided, single submitter
2222748	NM_006545.5(NPRL2):c.884G>A (p.Arg295Gln)	NPRL2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2434425	NM_006545.5(NPRL2):c.684-12TC[3]	NPRL2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · Orphanet: 6 · 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
NPRL2	Strong	Autosomal dominant	epilepsy, familial focal, with variable foci 2	17

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NPRL2	Orphanet:98820	Familial focal epilepsy with variable foci
CLCN2	Orphanet:307	Juvenile myoclonic epilepsy
CLCN2	Orphanet:363540	Leukoencephalopathy with mild cerebellar ataxia and white matter edema
CLCN2	Orphanet:404	Familial hyperaldosteronism type II
NPR2	Orphanet:329191	Tall stature-long halluces-multiple extra-epiphyses syndrome
NPR2	Orphanet:40	Acromesomelic dysplasia, Maroteaux type

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NPRL2	HGNC:24969	ENSG00000114388	Q8WTW4	GATOR1 complex protein NPRL2	gencc,clinvar
SPAG8	HGNC:14105	ENSG00000137098	Q99932	Sperm-associated antigen 8	clinvar
CLCN2	HGNC:2020	ENSG00000114859	P51788	Chloride channel protein 2	clinvar
NPR2	HGNC:7944	ENSG00000159899	P20594	Atrial natriuretic peptide receptor 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NPRL2	GATOR1 complex protein NPRL2	Catalytic component of the GATOR1 complex, a multiprotein complex that functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway.
SPAG8	Sperm-associated antigen 8	Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating.
CLCN2	Chloride channel protein 2	Voltage-gated and osmosensitive chloride channel.
NPR2	Atrial natriuretic peptide receptor 2	Receptor for the C-type natriuretic peptide NPPC/CNP hormone.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.25

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
Kinase	1	6.9×	0.273
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NPRL2	Other/Unknown	no		NPR2-like
SPAG8	Other/Unknown	no		Sperm-assoc_Ag8
CLCN2	Other/Unknown	no		ClC, Cl-channel-2, Cl-channel_core
NPR2	Kinase	yes	4.6.1.2	Prot_kinase_dom, A/G_cyclase, ANPR/GUC

Expression context

Cohort genes with no expression data: 0.

3 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar hemisphere	2
right hemisphere of cerebellum	2
right uterine tube	2
granulocyte	1
olfactory segment of nasal mucosa	1
tendon of biceps brachii	1
mucosa of transverse colon	1
sural nerve	1
tibial nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NPRL2	285	ubiquitous	marker	granulocyte, right hemisphere of cerebellum, cerebellar hemisphere
SPAG8	246	broad	marker	right uterine tube, tendon of biceps brachii, olfactory segment of nasal mucosa
CLCN2	181	broad	yes	mucosa of transverse colon, tibial nerve, sural nerve
NPR2	267	ubiquitous	marker	right uterine tube, right hemisphere of cerebellum, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CLCN2	1,250
NPRL2	1,222
SPAG8	1,151
NPR2	885

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NPRL2	Q8WTW4	10
CLCN2	P51788	8
SPAG8	Q99932	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NPR2	P20594	84.00

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Physiological factors	1	223.9×	0.022	NPR2
Amino acids regulate mTORC1	1	66.8×	0.034	NPRL2
Stimuli-sensing channels	1	45.3×	0.034	CLCN2
Cardiac conduction	1	36.2×	0.034	NPR2
Muscle contraction	1	25.7×	0.038	NPR2

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
vestibulocochlear nerve maturation	1	4213.0×	0.005	NPR2
regulation of aldosterone biosynthetic process	1	4213.0×	0.005	CLCN2
response to luteinizing hormone	1	2106.5×	0.005	NPR2
activation of meiosis involved in egg activation	1	2106.5×	0.005	NPR2
cell differentiation involved in salivary gland development	1	2106.5×	0.005	CLCN2
regulation of membrane depolarization during action potential	1	2106.5×	0.005	CLCN2
cumulus cell differentiation	1	1404.3×	0.005	NPR2
stabilization of membrane potential	1	1404.3×	0.005	CLCN2
gastric emptying	1	1404.3×	0.005	NPR2
c-di-GMP signaling	1	1404.3×	0.005	NPR2
negative regulation of kinase activity	1	1053.2×	0.005	NPRL2
negative regulation of meiotic cell cycle	1	1053.2×	0.005	NPR2
genitalia morphogenesis	1	842.6×	0.005	NPR2
acinar cell differentiation	1	842.6×	0.005	CLCN2
negative regulation of oocyte maturation	1	842.6×	0.005	NPR2
meiotic cell cycle process involved in oocyte maturation	1	702.2×	0.006	NPR2
female genitalia development	1	601.9×	0.006	NPR2
bone growth	1	601.9×	0.006	NPR2
growth plate cartilage development	1	526.6×	0.006	NPR2
cellular response to cGMP	1	526.6×	0.006	NPR2
response to fibroblast growth factor	1	526.6×	0.006	NPR2
response to salt	1	526.6×	0.006	NPR2
lymph vessel development	1	468.1×	0.006	NPR2
vascular wound healing	1	468.1×	0.006	NPR2
axonogenesis involved in innervation	1	421.3×	0.006	NPR2
cellular response to peptide	1	421.3×	0.006	NPR2
vacuole organization	1	383.0×	0.006	NPR2
cGMP biosynthetic process	1	351.1×	0.006	NPR2
cellular hypotonic response	1	351.1×	0.006	CLCN2
receptor guanylyl cyclase signaling pathway	1	324.1×	0.006	NPR2

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NPRL2	0	0
SPAG8	0	0
CLCN2	0	0
NPR2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
NPR2	11	Binding:11
CLCN2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NPR2	4.6.1.2	guanylate cyclase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	0
D	Druggable family + AlphaFold only, no drug	1	NPR2
E	Difficult family or no structure, no drug	3	NPRL2, SPAG8, CLCN2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NPRL2	0	—
SPAG8	0	—
CLCN2	1	—
NPR2	11	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.