NPRL3

Chr 16AD

NPR3 like, GATOR1 complex subunit

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

The protein functions as a component of the GATOR1 complex that inhibits mTORC1 signaling by acting as a GTPase activating protein for Rag complexes in response to amino acid depletion. Mutations cause familial focal epilepsy with variable foci 3, inherited in an autosomal dominant pattern. The pathogenic mechanism involves disruption of the amino acid-sensing mTORC1 pathway regulation at the lysosomal membrane.

OMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismADLOEUF 0.491 OMIM phenotype
Clinical SummaryNPRL3
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Gene-Disease Validity (ClinGen)
focal epilepsy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Moderate LoF intolerance
LoF Constraint
0.49LOEUF
pLI 0.190
Z-score 3.42
OE 0.25 (0.140.49)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
1.84Z-score
OE missense 0.72 (0.650.80)
245 obs / 340.4 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.25 (0.140.49)
00.351.4
Missense OE0.72 (0.650.80)
00.61.4
Synonymous OE1.02
01.21.6
LoF obs/exp: 6 / 24.1Missense obs/exp: 245 / 340.4Syn Z: -0.15
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
strongNPRL3-related familial focal epilepsy with or without focal cortical dysplasiaLOFAD
DN
0.4388th %ile
GOF
0.3788th %ile
LOF
0.4528th %ile

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOF1 literature citation · LOEUF 0.49

Literature Evidence

LOFResected dysplastic brain tissue from 3 patients with truncating mutations showed a 50% decrease in NPRL3, consistent with haploinsufficiency, as well as evidence of activation of the mTOR pathway.PMID:26285051

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

0 submitted variants 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.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

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Clinical Literature
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