NPRL2
protein-codingNPR2 like, GATOR1 complex subunit, the group of GATOR1 subcomplex
Gene summary
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]
- TUSC4
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~3.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0020310
Submitter: Illumina
Inheritance Pattern: AD
Disease ID:MONDO:0014924
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0020310
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0014924
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0005384
Submitter: ClinGen
*NPRL2* was first reported in relation to autosomal dominant focal epilepsy, a form of epilepsy characterized by seizures that are localized to one area or side of the brain, in 2016 (Ricos et al., PMID: 26505888). Of note, *NPRL2* is a member of the GATOR1 complex, which also includes *DEPDC5* and *NPRL3*. Each of these genes have an asserted relationship with autosomal dominant focal epilepsy (PMID: 23542697, 26505888). Ten variants in *NPRL2* (4 missense, 2 splice site, 3 nonsense and 1 frameshift) that have been reported in 12 probands in eight publications are included in this curation (PMIDs: 26505888, 27173016, 28199897, 29281825, 30093711, 31835056, 34376795). Variants in this gene have been observed to segregate with disease in families, but with incomplete penetrance (PMIDs: 26505888, 27173016, 28199897, 34376795). Additionally, several individuals with focal epilepsy and variants in *NPRL2* have been reported to have focal cortical dysplasia (PMIDs: 27173016, 30093711, 29281825, 37259768). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. In summary, there is definitive evidence supporting the relationship between *NPRL2* and autosomal dominant focal epilepsy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Epilepsy GCEP on the meeting date July 18, 2023 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0014924
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0014924
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NPRL2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_006545.5. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 4 | 11 | 15 | |||
| missense | 1 | 4 | 101 | 10 | 116 | |
| nonsense | 5 | 5 | 10 | |||
| start loss | 1 | 1 | ||||
| frameshift | 5 | 5 | 1 | 11 | ||
| splice donor/acceptor (+/-2bp) | 2 | 5 | 3 | 10 | ||
| Total | 13 | 20 | 109 | 21 | 0 | 163 |
Highest pathogenic variant AF is 0.0000041050453
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_006536.3 | 11 | MANE Select | |
| Ensembl | ENSP00000232501.3 | 11 | MANE Select | |
| Ensembl | ENSP00000396172.1 | 3 | Standard | |
| Ensembl | ENSP00000412779.1 | 3 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- mTOR signaling pathway - Homo sapiens (human)
Biological Process
- protein phosphorylation
- cellular response to nitrogen starvation
- positive regulation of autophagy
- negative regulation of TOR signaling
- negative regulation of kinase activity
Molecular Function
- protein kinase activity
- GTPase activator activity
- protein binding
Cellular Component
- lysosomal membrane
- GATOR1 complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000232501
- Coding exons
- 11
- Length
- 3762
- Individuals with no LoFs
- 125727
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 13
- Defined
- 125740
- p
- 0.0000517
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.64 | 155 | 224 | 0.692 | 0.0000133 | 2493 |
| Missense (PolyPhen) | 49 | 82.55 | 0.59358 | 873 | ||
| Synonymous | 0.413 | 84 | 89.0 | 0.944 | 0.00000508 | 722 |
| Loss of Function | 3.40 | 5 | 22.4 | 0.223 | 0.00000113 | 251 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0.00028 | 0.00028 | rare |
| European (Non-Finnish) | 0.000035 | 0.000035 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the TORC1 pathway. The GATOR1 complex strongly increases GTP hydrolysis by RRAGA and RRAGB within RRAGC-containing heterodimers, thereby deactivating RRAGs, releasing mTORC1 from lysosomal surface and inhibiting mTORC1 signaling. The GATOR1 complex is negatively regulated by GATOR2 the other GATOR subcomplex in this amino acid-sensing branch of the TORC1 pathway. {ECO:0000269|PubMed:23723238}.;
- Disease
- DISEASE: Epilepsy, familial focal, with variable foci 2 (FFEVF2) [MIM:617116]: An autosomal dominant form of epilepsy characterized by focal seizures arising from different cortical regions, including the temporal, frontal, parietal, and occipital lobes. Seizure types commonly include temporal lobe epilepsy, frontal lobe epilepsy, and nocturnal frontal lobe epilepsy. Some patients may have intellectual disability or autism spectrum disorders. Seizure onset usually occurs in the first or second decades, although later onset has been reported, and there is phenotypic variability within families. A subset of patients have structural brain abnormalities. Penetrance of the disorder is incomplete. {ECO:0000269|PubMed:26505888, ECO:0000269|PubMed:27173016}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.117
Intolerance Scores
- RVIS EVS
- -0.43
- RVIS percentile EVS
- 25.15
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.824
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |