Epilepsy, familial focal, with variable foci 3

Summary

Epilepsy, familial focal, with variable foci 3 (MONDO:0014925) is a disease caused by NPRL3 (GenCC Strong), with 4 cohort genes.

At a glance

• Causal gene: NPRL3 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 928

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	epilepsy, familial focal, with variable foci 3
Mondo ID	MONDO:0014925
OMIM	617118
DOID	DOID:0081423
UMLS	C4310708
MedGen	934675
GARD	0018204
Is cancer (heuristic)	no

Also known as: epilepsy, familial focal, with variable foci 3 · epilepsy, familial focal, with variable foci 3; FFEVF3 · epilepsy, familial focal, with variable foci caused by mutation in NPRL3 · epilepsy, familial focal, with variable foci type 3 · FFEVF3 · NPRL3 epilepsy, familial focal, with variable foci

Data availability: 928 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 3

Related subtypes (3): epilepsy, familial focal, with variable foci 2, 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

600 retrieved; paginated sample, class counts are floors:

248 uncertain significance, 222 likely benign, 74 pathogenic, 23 likely pathogenic, 13 benign, 12 conflicting classifications of pathogenicity, 7 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1012387	NM_001077350.3(NPRL3):c.189-1G>A	HBA-LCR	Pathogenic	criteria provided, multiple submitters, no conflicts
1066351	NM_001077350.3(NPRL3):c.318+1G>A	HBA-LCR	Pathogenic	criteria provided, multiple submitters, no conflicts
1069081	NM_001077350.3(NPRL3):c.622del (p.Tyr208fs)	HBA-LCR	Pathogenic	criteria provided, single submitter
1069552	NC_000016.10:g.92726del	HBA-LCR	Pathogenic	criteria provided, single submitter
1069967	NM_001077350.3(NPRL3):c.726dup (p.Ile243fs)	HBA-LCR	Pathogenic	criteria provided, single submitter
1072659	NM_001077350.3(NPRL3):c.1174C>T (p.Gln392Ter)	HBA-LCR	Pathogenic	criteria provided, single submitter
1072921	NM_001077350.3(NPRL3):c.258del (p.Lys87fs)	HBA-LCR	Pathogenic	criteria provided, single submitter
1073416	NM_001077350.3(NPRL3):c.15del (p.Ser6fs)	HBA-LCR	Pathogenic	criteria provided, single submitter
1076033	NM_001077350.3(NPRL3):c.460C>T (p.Gln154Ter)	HBA-LCR	Pathogenic	criteria provided, single submitter
1184941	NM_001077350.3(NPRL3):c.1149del (p.Ala384fs)	HBA-LCR	Pathogenic	criteria provided, multiple submitters, no conflicts
1297749	NM_001077350.3(NPRL3):c.316C>T (p.Gln106Ter)	HBA-LCR	Pathogenic	criteria provided, single submitter
1323374	NM_001077350.3(NPRL3):c.419dup (p.Asn140fs)	HBA-LCR	Pathogenic	criteria provided, single submitter
1325822	NM_001077350.3(NPRL3):c.922C>T (p.Gln308Ter)	HBA-LCR	Pathogenic	criteria provided, multiple submitters, no conflicts
1353907	NM_001077350.3(NPRL3):c.518dup (p.Gln174fs)	HBA-LCR	Pathogenic	criteria provided, single submitter
1385105	NM_001077350.3(NPRL3):c.280del (p.Val94fs)	HBA-LCR	Pathogenic	criteria provided, single submitter
1404496	NM_001077350.3(NPRL3):c.78C>A (p.Tyr26Ter)	HBA-LCR	Pathogenic	criteria provided, single submitter
1410974	NM_001077350.3(NPRL3):c.745G>T (p.Glu249Ter)	HBA-LCR	Pathogenic	criteria provided, single submitter
1419387	NM_001077350.3(NPRL3):c.767+1del	HBA-LCR	Pathogenic	criteria provided, single submitter
1443589	NM_001077350.3(NPRL3):c.1178dup (p.Met393fs)	HBA-LCR	Pathogenic	criteria provided, single submitter
1452513	NM_001077350.3(NPRL3):c.1480G>T (p.Glu494Ter)	HBA-LCR	Pathogenic	criteria provided, single submitter
1455249	NM_001077350.3(NPRL3):c.274C>T (p.Arg92Ter)	HBA-LCR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457332	NM_001077350.3(NPRL3):c.898C>T (p.Gln300Ter)	HBA-LCR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1465304	NM_001077350.3(NPRL3):c.119-1G>C	HBA-LCR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1878416	NM_001077350.3(NPRL3):c.1184_1188del (p.Val395fs)	HBA-LCR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1972282	NM_001077350.3(NPRL3):c.768-1G>A	HBA-LCR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2020251	NM_001077350.3(NPRL3):c.269del (p.Asn90fs)	HBA-LCR	Pathogenic	criteria provided, single submitter
2026233	NM_001077350.3(NPRL3):c.799G>T (p.Glu267Ter)	HBA-LCR	Pathogenic	criteria provided, single submitter
2032953	NM_001077350.3(NPRL3):c.1078del (p.Asp360fs)	HBA-LCR	Pathogenic	criteria provided, single submitter
2087315	NM_001077350.3(NPRL3):c.169G>T (p.Glu57Ter)	HBA-LCR	Pathogenic	criteria provided, single submitter
2132237	NM_001077350.3(NPRL3):c.1093del (p.Ala366fs)	HBA-LCR	Pathogenic	criteria provided, single submitter

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
NPRL3	Strong	Autosomal dominant	epilepsy, familial focal, with variable foci 3	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NPRL3	Orphanet:98820	Familial focal epilepsy with variable foci

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NPRL3	HGNC:14124	ENSG00000103148	Q12980	GATOR1 complex protein NPRL3	gencc,clinvar
SNRNP25	HGNC:14161	ENSG00000161981	Q9BV90	U11/U12 small nuclear ribonucleoprotein 25 kDa protein	clinvar
MVP-DT	HGNC:56029	ENSG00000238045		MVP divergent transcript	clinvar
MPG	HGNC:7211	ENSG00000103152	P29372	DNA-3-methyladenine glycosylase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NPRL3	GATOR1 complex protein NPRL3	As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway.
MPG	DNA-3-methyladenine glycosylase	Hydrolysis of the deoxyribose N-glycosidic bond to excise 3-methyladenine, and 7-methylguanine from the damaged DNA polymer formed by alkylation lesions.

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
Enzyme (other)	1	3.0×	0.404
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NPRL3	Other/Unknown	no		Npr3, HTH_NPRL3
SNRNP25	Other/Unknown	no		Ubiquitin-like_dom, Ubiquitin-like_domsf, SNRNP25
MVP-DT	Other/Unknown	no
MPG	Enzyme (other)	yes	3.2.2.21	MPG, Formyl_transferase-like_C_sf, MPG_sf

Expression context

Cohort genes with no expression data: 0.

4 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
blood	1
hindlimb stylopod muscle	1
right uterine tube	1
apex of heart	1
pons	1
prefrontal cortex	1
mucosa of transverse colon	1
oviduct epithelium	1
tendon of biceps brachii	1
ascending aorta	1
descending thoracic aorta	1
thoracic aorta	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NPRL3	276	ubiquitous	marker	blood, hindlimb stylopod muscle, right uterine tube
SNRNP25	280	ubiquitous	marker	pons, apex of heart, prefrontal cortex
MVP-DT	191		marker	oviduct epithelium, mucosa of transverse colon, tendon of biceps brachii
MPG	280	ubiquitous	marker	ascending aorta, thoracic aorta, descending thoracic aorta

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NPRL3	1,511
SNRNP25	1,009
MPG	983
MVP-DT	0

Intra-cohort edges

A	B	Sources
MPG	SNRNP25	string_interaction
NPRL3	SNRNP25	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NPRL3	Q12980	10
MPG	P29372	9
SNRNP25	Q9BV90	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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
Depurination	1	543.8×	0.008	MPG
Resolution of Abasic Sites (AP sites)	1	380.7×	0.008	MPG
Displacement of DNA glycosylase by APEX1	1	346.1×	0.008	MPG
Base-Excision Repair, AP Site Formation	1	292.8×	0.008	MPG
Base Excision Repair	1	237.9×	0.008	MPG
mRNA Splicing - Minor Pathway	1	74.6×	0.017	SNRNP25
Recognition and association of DNA glycosylase with site containing an affected purine	1	68.0×	0.017	MPG
Cleavage of the damaged purine	1	68.0×	0.017	MPG
Amino acids regulate mTORC1	1	66.8×	0.017	NPRL3
DNA Repair	1	32.8×	0.030	MPG

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
depurination	1	1404.3×	0.009	MPG
DNA alkylation repair	1	510.7×	0.010	MPG
aorta morphogenesis	1	295.6×	0.010	NPRL3
cardiac muscle tissue development	1	295.6×	0.010	NPRL3
ventricular septum development	1	165.2×	0.013	NPRL3
base-excision repair	1	156.0×	0.013	MPG
negative regulation of TORC1 signaling	1	108.0×	0.014	NPRL3
cellular response to amino acid starvation	1	106.0×	0.014	NPRL3
roof of mouth development	1	82.6×	0.016	NPRL3
positive regulation of autophagy	1	69.3×	0.017	NPRL3
mRNA splicing, via spliceosome	1	30.5×	0.034	SNRNP25
RNA splicing	1	29.4×	0.034	SNRNP25

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) 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
MPG	MITOXANTRONE HYDROCHLORIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MPG	2	4
NPRL3	0	0
SNRNP25	0	0
MVP-DT	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MITOXANTRONE HYDROCHLORIDE	4	MPG
GOSSYPOL	3	MPG

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MPG	12	Binding:11, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MPG	3.2.2.21	DNA-3-methyladenine glycosylase II

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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)
MITOXANTRONE HYDROCHLORIDE	4	MPG
GOSSYPOL	3	MPG

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MPG
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	3	NPRL3, SNRNP25, MVP-DT

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NPRL3	0	—
SNRNP25	0	—
MVP-DT	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.