NPRL3

Chr 16AD

NPR3 like, GATOR1 complex subunit

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

NCBI Gene: 8131 ENSG00000103148 UniProt: Q12980 OMIM: 600928

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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.491 OMIM phenotype

Clinical Summary— NPRL3

🧬

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.

📋

ClinVar Variants

190 unique Pathogenic / Likely Pathogenic· 510 VUS of 1171 total submissions

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — NPRL3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

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?

1.84Z-score

OE missense 0.72 (0.65–0.80)

245 obs / 340.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.25 (0.14–0.49)

0≤0.351.4

Missense OE?0.72 (0.65–0.80)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

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

This gene — mechanism propensity

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 · 70% of P/LP variants are LoF · LOEUF 0.49 · ClinGen HI: Sufficient evidence for dosage pathogenicity

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.1

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

References

1.PMID 26285051 ↗

ClinVar Variant Classifications

1171 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic133

Likely Pathogenic57

VUS510

Likely Benign352

Benign71

Conflicting32

133

Pathogenic

Likely Pathogenic

510

VUS

352

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	84	1	48	0	133
Likely Pathogenic	49	0	8	0	57
VUS	17	406	78	9	510
Likely Benign	3	7	168	174	352
Benign	2	4	61	4	71
Conflicting	—				32
Total	155	418	363	187	1,155

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

View in ClinVar →

52 pathogenic / likely-pathogenic (of 79) ClinVar copy-number / structural variants overlap NPRL3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →