NPRL2

Chr 3AD

NPR2 like, GATOR1 complex subunit

Also known as: FFEVF2, NPR2, NPR2L, TUSC4

NCBI Gene: 10641ENSG00000114388UniProt: Q8WTW4

Enables GTPase activator activity. Involved in cellular response to amino acid starvation; negative regulation of TORC1 signaling; and negative regulation of kinase activity. Part of GATOR1 complex. Is active in lysosomal membrane. Implicated in familial focal epilepsy with variable foci 2. [provided by Alliance of Genome Resources, Jul 2025]

Primary Disease Associations & Inheritance

Epilepsy, familial focal, with variable foci 2MIM #617116
AD
165
ClinVar variants
34
Pathogenic / LP
0.39
pLI score
1
Active trials
Clinical Summary— NPRL2
🧬
Gene-Disease Validity (ClinGen)
focal epilepsy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.22) despite low pLI — interpret in context.
📋
ClinVar Variants
34 Pathogenic / Likely Pathogenic· 98 VUS of 165 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.47LOEUF
pLI 0.388
Z-score 3.40
OE 0.22 (0.12–0.47)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.64Z-score
OE missense 0.69 (0.61–0.79)
155 obs / 224.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.22 (0.12–0.47)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.69 (0.61–0.79)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.94
0≤1.21.6
LoF obs/exp: 5 / 22.4Missense obs/exp: 155 / 224.1Syn Z: 0.41

ClinVar Variant Classifications

165 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic19
Likely Pathogenic15
VUS98
Likely Benign17
Benign9
Conflicting7
19
Pathogenic
15
Likely Pathogenic
98
VUS
17
Likely Benign
9
Benign
7
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
6
1
12
0
19
Likely Pathogenic
9
2
4
0
15
VUS
1
88
8
1
98
Likely Benign
0
5
7
5
17
Benign
0
0
8
1
9
Conflicting
—7
Total1696397165

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

NPRL2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

NPRL2-related familial focal epilepsy with or without focal cortical dysplasia

strong
ADLoss Of FunctionAbsent Gene Product, Decreased Gene Product Level
Dev. Disorders
G2P ↗
splice region variantframeshift variantmissense variant

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Epilepsy, familial focal, with variable foci 2

MIM #617116

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — NPRL2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The landscape of epilepsy-related GATOR1 variants.
Baldassari S et al.·Genet Med
2019
Clinical phenotype and genotype of NPRL2-related epilepsy: Four cases reports and literature review.
Zhang H et al.·Seizure
2024Review
NPRL2 promotes TRIM16-mediated ubiquitination degradation of Galectin-3 to prevent CD8(+)T lymphocyte cuproptosis in glioma.
Wang F et al.·Cell Mol Life Sci
2024
Novel GATOR1 variants in focal epilepsy.
Kovačević M et al.·Epilepsy Behav
2023
A splicing variation in NPRL2 causing familial focal epilepsy with variable foci: additional cases and literature review.
Zhang J et al.·J Hum Genet
2022Review
Clinical and genetic features of GATOR1 complex-associated epilepsy.
Yin K et al.·J Med Genet
2023
NPRL2 down-regulation facilitates the growth of hepatocellular carcinoma via the mTOR pathway and autophagy suppression.
Wang YC et al.·Hepatol Commun
2022
Explosive onset focal epilepsies without cortical malformation: A review of a pediatric cohort with pathogenic variations in the GATOR1 complex (DEPDC5, NPRL3 and NPRL2).
Baer S et al.·Seizure
2025Review
mTOR signaling pathway genes in focal epilepsies.
Baulac S·Prog Brain Res
2016Review
High expression of NPRL2 is linked to poor prognosis in patients with prostate cancer.
Chen Z et al.·Hum Pathol
2018Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Epilepsy

Precision Medicine in the Treatment of Epilepsy

RECRUITING
NCT05450822Gitte Moos KnudsenStarted 2022-02-18
LevetiracetamLevetiracetam TabletsLamotrigine tablet

External Resources

Links to major genomics databases and tools