NPRL3

Chr 16

NPR3 like, GATOR1 complex subunit

Also known as: C16orf35, CGTHBA, FFEVF3, HS-40, MARE, NPR3, RMD11

NCBI Gene: 8131ENSG00000103148UniProt: Q12980

Predicted to enable GTPase activator activity. Involved in cellular response to amino acid starvation and negative regulation of TORC1 signaling. Part of GATOR1 complex. Is active in lysosomal membrane. Implicated in familial focal epilepsy with variable foci 3. [provided by Alliance of Genome Resources, Jul 2025]

Primary Disease Associations & Inheritance

UniProtEpilepsy, familial focal, with variable foci 3
1239
ClinVar variants
56
Pathogenic / LP
0.19
pLI score
0
Active trials
Clinical Summary— NPRL3
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.
📋
ClinVar Variants
56 Pathogenic / Likely Pathogenic· 161 VUS of 1239 total submissions
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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.
0.49LOEUF
pLI 0.190
Z-score 3.42
OE 0.25 (0.14–0.49)
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.
1.84Z-score
OE missense 0.72 (0.65–0.80)
245 obs / 340.4 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.0.25 (0.14–0.49)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.72 (0.65–0.80)
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.1.02
0≤1.21.6
LoF obs/exp: 6 / 24.1Missense obs/exp: 245 / 340.4Syn Z: -0.15

ClinVar Variant Classifications

1239 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic45
Likely Pathogenic11
VUS161
Likely Benign65
Conflicting2
45
Pathogenic
11
Likely Pathogenic
161
VUS
65
Likely Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
17
0
28
0
45
Likely Pathogenic
7
0
4
0
11
VUS
5
122
33
1
161
Likely Benign
1
2
33
29
65
Benign
0
0
0
0
0
Conflicting
—2
Total301249830284

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

View in ClinVar →

Protein Context — Lollipop Plot

NPRL3 · protein map & ClinVar variants

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

Gene2Phenotype Curations

NPRL3-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 variantstop lostmissense variant

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

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

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
Phenotypic and genotypic characterization of NPRL3-related epilepsy: Two case reports and literature review.
Yang D et al.·Epilepsia Open
2024Review
The clinical features of familial focal epilepsy with variable foci and NPRL3 gene variant.
Wang Y et al.·PLoS One
2023
Refining the electroclinical spectrum of NPRL3-related epilepsy: A novel multiplex family and literature review.
Dainelli A et al.·Epilepsia Open
2023Review
The clinical, imaging, pathological and genetic landscape of bottom-of-sulcus dysplasia.
Macdonald-Laurs E et al.·Brain
2024
Novel GATOR1 variants in focal epilepsy.
Kovačević M et al.·Epilepsy Behav
2023
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
Functional characterization of novel NPRL3 mutations identified in three families with focal epilepsy.
Du S et al.·Sci China Life Sci
2023Functional
NPRL3 loss alters neuronal morphology, mTOR localization, cortical lamination and seizure threshold.
Iffland PH et al.·Brain
2022
Psychoses of Epilepsy: Unravelling the Phenotypic and Genotypic Features.
Rayner G et al.·Ann Neurol
2025
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools