NPRL2

Summary

NPRL2 (NPR2 like, GATOR1 complex subunit, HGNC:24969) is a protein-coding gene on chromosome 3p21.31, encoding GATOR1 complex protein NPRL2 (Q8WTW4). Catalytic component of the GATOR1 complex, a multiprotein complex that functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway.

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.

Source: NCBI Gene 10641 — RefSeq curated summary.

At a glance

• Gene–disease (curated): focal epilepsy (Definitive, ClinGen) — +6 more curated relationships
• GWAS associations: 10
• Clinical variants (ClinVar): 906 total — 69 pathogenic, 48 likely-pathogenic
• Phenotypes (HPO): 29
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 1 cancer types
• MANE Select transcript: NM_006545

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24969
Approved symbol	NPRL2
Name	NPR2 like, GATOR1 complex subunit
Location	3p21.31
Locus type	gene with protein product
Status	Approved
Aliases	NPR2L, NPR2
Ensembl gene	ENSG00000114388
Ensembl biotype	protein_coding
OMIM	607072
Entrez	10641

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 11 retained_intron, 9 protein_coding, 7 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000232501, ENST00000418825, ENST00000429366, ENST00000433381, ENST00000433999, ENST00000448302, ENST00000451194, ENST00000461020, ENST00000467294, ENST00000469839, ENST00000476064, ENST00000479512, ENST00000480296, ENST00000487632, ENST00000492805, ENST00000493465, ENST00000493907, ENST00000667046, ENST00000667631, ENST00000671487, ENST00000894718, ENST00000894719, ENST00000894720, ENST00000931005, ENST00000931006, ENST00000966295, ENST00000966296, ENST00000966297

RefSeq mRNA: 1 — MANE Select: NM_006545 NM_006545

CCDS: CCDS2826

Canonical transcript exons

ENST00000232501 — 11 exons

Exon	Start	End
ENSE00001400146	50350575	50350775
ENSE00003503554	50349665	50349833
ENSE00003523734	50348527	50348563
ENSE00003524391	50347759	50347901
ENSE00003525632	50348124	50348241
ENSE00003577849	50349386	50349494
ENSE00003579466	50347330	50347673
ENSE00003599758	50349931	50350022
ENSE00003603151	50348317	50348410
ENSE00003607835	50348685	50348782
ENSE00003625830	50348874	50349010

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 95.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.6800 / max 135.7269, expressed in 1807 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
42336	18.6800	1807

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	95.76	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.26	gold quality
cerebellar hemisphere	UBERON:0002245	93.06	gold quality
cerebellar cortex	UBERON:0002129	93.01	gold quality
body of pancreas	UBERON:0001150	92.21	gold quality
cerebellum	UBERON:0002037	92.16	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	91.75	gold quality
hindlimb stylopod muscle	UBERON:0004252	91.48	gold quality
pituitary gland	UBERON:0000007	91.39	gold quality
adenohypophysis	UBERON:0002196	91.30	gold quality
prefrontal cortex	UBERON:0000451	90.48	gold quality
right frontal lobe	UBERON:0002810	90.34	gold quality
apex of heart	UBERON:0002098	90.14	gold quality
pancreas	UBERON:0001264	89.34	gold quality
Brodmann (1909) area 9	UBERON:0013540	89.15	gold quality
blood	UBERON:0000178	89.11	gold quality
right ovary	UBERON:0002118	89.00	gold quality
cingulate cortex	UBERON:0003027	88.94	gold quality
gastrocnemius	UBERON:0001388	88.86	gold quality
nucleus accumbens	UBERON:0001882	88.81	gold quality
anterior cingulate cortex	UBERON:0009835	88.81	gold quality
vastus lateralis	UBERON:0001379	88.78	gold quality
gluteal muscle	UBERON:0002000	88.77	gold quality
mucosa of transverse colon	UBERON:0004991	88.74	gold quality
body of stomach	UBERON:0001161	88.71	gold quality
muscle of leg	UBERON:0001383	88.66	gold quality
frontal cortex	UBERON:0001870	88.63	gold quality
parotid gland	UBERON:0001831	88.62	gold quality
left ovary	UBERON:0002119	88.62	gold quality
cortical plate	UBERON:0005343	88.59	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-100618	yes	289.47
E-ANND-3	yes	7.16

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

7 targeting NPRL2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-203A-3P	99.49	70.56	2806
HSA-MIR-511-5P	98.97	70.94	2268
HSA-MIR-4764-5P	98.88	65.53	894
HSA-MIR-4305	97.94	68.63	533
HSA-MIR-6791-3P	97.45	64.31	1123
HSA-MIR-6829-3P	97.45	64.31	1137

Literature-anchored findings (GeneRIF, showing 32)

• NPRL2 is a multiple tumor suppressor gene. (PMID:15374952)
• Expression of NPRL2 was significantly and reciprocally correlated to cisplatin sensitivity. (PMID:17018626)
• TUSC4/NPRL2, a novel PDK1-interacting protein, plays a role in regulating the Src/PDK1 signaling pathway and cell sensitivity to multiple cancer chemotherapeutic drugs. (PMID:18616680)
• Down-regulation of RBSP3/CTDSPL, NPRL2/G21, RASSF1A, ITGA9, HYAL1 and HYAL2 genes in non-small cell lung cancer (PMID:19140316)
• Our results suggest that NPRL2 mRNA expression has prognostic significance for the survival of patients with HCC. (PMID:19274676)
• Data indicate that Npr2, a homolog of human NPRL2, is a phosphorylation-dependent target of the SCF(Grr1) E3 ubiquitin ligase that plays a role in cell growth on some nitrogen sources. (PMID:20154027)
• tumor suppressor genes RBSP3/CTDSPL, NPRL2/G21 and RASSF1A are downregulated in primary non-small cell lung cancer (PMID:20193080)
• Lower NPRL2 expression was observed significantly more frequently in poorly differentiated tumor samples than in highly or moderately differentiated colon tumors. (PMID:23079973)
• NPRL2 expression is negatively related with the survival of osteosarcoma patients, indicating its value as a prognosis factor of osteosarcoma. (PMID:23321467)
• NPRL2 mRNA blood levels could be a potentially useful marker for the detection of early stage adenomas and colorectal cancers. (PMID:24521741)
• Decreased expression of NPRL2 is associated with renal cancer. (PMID:24789683)
• Results provide a set of genetic and biologic proofs that TUSC4 functions as a bona fide tumor suppressor by regulating the protein stability and function of BRCA1 in breast cancer. (PMID:25480944)
• NPRL2 enhances sensitivity to oxaliplatin in colon cancer cells. (PMID:25777765)
• Data confirmed NPRL2 was downregulated in gliomas. More importantly, NPRL2 was able to inhibit cell proliferation in vitro and repress tumorigenicity in vivo, suggesting its role as a tumor suppressor. (PMID:26455908)
• NPRL2 mutations are significant cause of focal epilepsy. (PMID:26505888)
• The positive regulation of mTORC1 activity by NPRL2 is mediated through NPRL2 interaction with Raptor. (PMID:26582740)
• This study demonstrated that NPRL2 mutation in familial focal epilepsies and focal cortical dysplasia. (PMID:27173016)
• We found no correlation between the DLEC1, TUSC4 and MLH1 gene expression and NSCLC patient characteristics (gender, age and smoking) or cancer histopathology. No significant differences in the gene expression among NSCLC subtypes indicate the weakness of DLEC1, TUSC4 and MLH1 expression analysis as potential differentiating markers of NSCLC subtypes in the Polish population. (PMID:28674222)
• these results demonstrate a new role for the NPRL2, distinct from its function in mTORC1 regulation. (PMID:29127423)
• The expression level of NPRL2 was significantly up-regulated in prostate cancer and its high expression was correlated with poor prognosis. (PMID:29458069)
• NPRL2 overexpression enhances sensitivity to CPT-11 treatment in colon cancer cells. (PMID:29519997)
• overall, 63 distinct variants were identified: 53 in DEPDC5, three in NPRL2 and seven in NPRL3 . Among these, 46 were novel (including 39 single nucleotide variants and seven CNVs) and 16 were newly defined as recurrent variants; 34 were loss-of-function (LoF) variants (nonsense, splice-site, frameshift indels and CNVs). (PMID:30093711)
• The high levels of NPRL2 expression in castrate-resistant prostate cancer promote resistance to Everolimus by enhancing autophagy. (PMID:30178500)
• Arg-78 of Nprl2 catalyzes GATOR1-stimulated GTP hydrolysis by the Rag GTPases. (PMID:30651352)
• NPRL2 promotes docetaxel chemoresistance in castration resistant prostate cancer cells by regulating autophagy through the mTOR pathway. (PMID:32234375)
• NPRL2 reduces the niraparib sensitivity of castration-resistant prostate cancer via interacting with UBE2M and enhancing neddylation. (PMID:33905671)
• A splicing variation in NPRL2 causing familial focal epilepsy with variable foci: additional cases and literature review. (PMID:34376795)
• FOXO1 inhibits prostate cancer cell proliferation via suppressing E2F1 activated NPRL2 expression. (PMID:34459063)
• Nitrogen Permease Regulator Like-2 (NPRL2 ) truncating mutation causes Ohtahara syndrome with incomplete penetrance: expanding the genotype-phenotype correlations. (PMID:35731010)
• NPRL2 down-regulation facilitates the growth of hepatocellular carcinoma via the mTOR pathway and autophagy suppression. (PMID:36321403)
• Risk signature identification and NPRL2 affects sunitinib sensitivity in clear cell renal cell carcinoma. (PMID:37121122)
• Seizure features and outcomes in 50 children with GATOR1 variants: A retrospective study, more favorable for epilepsy surgery. (PMID:37259768)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	nprl2	ENSDARG00000059613
mus_musculus	Nprl2	ENSMUSG00000010057
rattus_norvegicus	Nprl2	ENSRNOG00000021660
drosophila_melanogaster	Nprl2	FBGN0030800
caenorhabditis_elegans		WBGENE00018635

Protein

Protein identifiers

GATOR1 complex protein NPRL2 — Q8WTW4 (reviewed: Q8WTW4)

Alternative names: Gene 21 protein, Nitrogen permease regulator 2-like protein, Tumor suppressor candidate 4

All UniProt accessions (4): Q8WTW4, A0A590UJY0, F2Z2R8, F2Z3D4

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic component of the GATOR1 complex, a multiprotein complex that functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway. In response to amino acid depletion, the GATOR1 complex has GTPase activating protein (GAP) activity and strongly increases GTP hydrolysis by RagA/RRAGA (or RagB/RRAGB) within heterodimeric Rag complexes, thereby turning them into their inactive GDP-bound form, releasing mTORC1 from lysosomal surface and inhibiting mTORC1 signaling. In the presence of abundant amino acids, the GATOR1 complex is ubiquitinated and inhibited by GATOR2. Within the GATOR1 complex, NPRL2 constitutes the catalytic subunit that mediates the GTPase activator activity and under methionine-sufficient conditions, the GTPase activator activity is inhibited by PRMT1 through methylation and consequently inducing timely mTORC1 activation. Suppresses Src-dependent tyrosine phosphorylation and activation of PDPK1 and its downstream signaling. Down-regulates PDPK1 kinase activity by interfering with tyrosine phosphorylation at ‘Tyr-9’, ‘Tyr-373’ and ‘Tyr-376’ residues. May act as a tumor suppressor. Suppresses cell growth and enhances sensitivity to various anticancer drugs.

Subunit / interactions. Within the GATOR complex, component of the GATOR1 subcomplex, made of DEPDC5, NPRL2 and NPRL3. GATOR1 mediates the strong interaction of the GATOR complex with small GTPases Rag (RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and/or RagD/RRAGD) heterodimers. GATOR1 interacts with GPR155/LYCHOS; interaction takes place in presence of cholesterol and prevents interaction between GATOR1 and KICSTOR. Interacts with PDPK1.

Subcellular location. Lysosome membrane.

Tissue specificity. Most abundant in skeletal muscle, followed by brain, liver and pancreas, with lower amounts in lung, kidney, placenta and heart. Expressed in the frontal lobe cortex as well as in the temporal, parietal, and occipital lobes. Expressed in most lung cancer cell lines tested.

Post-translational modifications. In the presence of abundant amino acids, ubiquitinated at Lys-158 and Lys-357 via ‘Lys-6’-linked ubiquitination by the WDR24 component of the GATOR2 complex, thereby inhibiting the GATOR1 complex and promoting mTORC1 activation. Asymmetric dimethylation at Arg-78 by PRMT1 inhibits the GTPase activator activity of the GATOR1 complex and consequently inducing timely mTORC1 activation under methionine-sufficient conditions.

Disease relevance. Inactivating mutations and truncating deletions in the genes encoding GATOR1 proteins, including NPRL2, are detected in glioblastoma and ovarian tumors and are associated with loss of heterozygosity events. Inactivation of GATOR1 proteins promotes constitutive localization of mTORC1 to the lysosomal membrane and blocks mTORC1 inactivation following amino acid withdrawal. 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. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The arginine finger is critical for the GTPase-activating mechanism.

Similarity. Belongs to the NPR2 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8WTW4-1	1	yes
Q8WTW4-2	2

RefSeq proteins (1): NP_006536* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009348	NPR2-like	Family

Pfam: PF06218

UniProt features (69 total): strand 18, helix 18, mutagenesis site 14, sequence variant 4, turn 4, splice variant 3, cross-link 2, chain 1, region of interest 1, binding site 1, sequence conflict 1, site 1, modified residue 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
9V0J	ELECTRON MICROSCOPY	2.97
8FW5	ELECTRON MICROSCOPY	3.08
9O5A	ELECTRON MICROSCOPY	3.2
9O5D	ELECTRON MICROSCOPY	3.34
7T3B	ELECTRON MICROSCOPY	3.9
6CES	ELECTRON MICROSCOPY	4
7T3A	ELECTRON MICROSCOPY	4
7T3C	ELECTRON MICROSCOPY	4
6CET	ELECTRON MICROSCOPY	4.4
9O5E	ELECTRON MICROSCOPY	5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WTW4-F1	69.38	0.00

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 124 (arginine finger)

Ligand- & substrate-binding residues (1): 78

Post-translational modifications (3): 78, 158, 357

Mutagenesis-validated functional residues (14):

Position	Phenotype
17–21	in rl1 mutant; abolished ability of the gator1 complex to inhibit mtorc1 signaling.
20	abolished gtpase activating protein activity toward raga/rraga.
78	abolished gtpase activating protein activity toward raga/rraga.
117–121	in rl2 mutant; does not affect ability of the gator1 complex to inhibit mtorc1 signaling.
158	decreased ubiquitination by the gator2 complex.
279	does not affect the gtpase activating protein activity of the gator1 complex.
295	does not affect the gtpase activating protein activity of the gator1 complex.
300	does not affect the gtpase activating protein activity of the gator1 complex.
311	does not affect the gtpase activating protein activity of the gator1 complex.
324	does not affect the gtpase activating protein activity of the gator1 complex.
328	does not affect ubiquitination by the gator2 complex.
343	does not affect the gtpase activating protein activity of the gator1 complex.
357	decreased ubiquitination by the gator2 complex.
368	does not affect the gtpase activating protein activity of the gator1 complex.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9639288	Amino acids regulate mTORC1

MSigDB gene sets: 663 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, GOBP_SINGLE_FERTILIZATION, GOBP_CHROMOSOME_ORGANIZATION, GOBP_DIGESTION, GOBP_NEGATIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_POSITIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_CELL_MATURATION, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, WANG_CLIM2_TARGETS_UP, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_REGULATION_OF_BLOOD_PRESSURE, TGCGCANK_UNKNOWN

GO Biological Process (12): positive regulation of autophagy (GO:0010508), negative regulation of kinase activity (GO:0033673), cellular response to amino acid starvation (GO:0034198), negative regulation of TORC1 signaling (GO:1904262), cytoplasmic translation (GO:0002181), cellular response to nutrient levels (GO:0031669), TORC1 signaling (GO:0038202), negative regulation of translational initiation (GO:0045947), positive regulation of translational initiation (GO:0045948), cellular response to methionine (GO:0061431), protein localization to lysosome (GO:0061462), positive regulation of TORC1 signaling (GO:1904263)

GO Molecular Function (2): GTPase activator activity (GO:0005096), protein binding (GO:0005515)

GO Cellular Component (5): lysosomal membrane (GO:0005765), vacuolar membrane (GO:0005774), GATOR1 complex (GO:1990130), lysosome (GO:0005764), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Cellular response to starvation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
TORC1 signaling	2
regulation of TORC1 signaling	2
translational initiation	2
regulation of translational initiation	2
autophagy	1
positive regulation of catabolic process	1
regulation of autophagy	1
kinase activity	1
negative regulation of phosphorylation	1
negative regulation of catalytic activity	1
regulation of kinase activity	1
cellular response to starvation	1
response to amino acid starvation	1
negative regulation of TOR signaling	1
translation	1
response to nutrient levels	1
cellular response to stimulus	1
TOR signaling	1
negative regulation of translation	1
positive regulation of translation	1
cellular response to nutrient	1
cellular response to amino acid stimulus	1
cellular response to nitrogen compound	1
cellular response to oxygen-containing compound	1
response to methionine	1
protein localization to vacuole	1
positive regulation of TOR signaling	1
GTPase activity	1
enzyme activator activity	1
GTPase regulator activity	1
binding	1
lysosome	1
lytic vacuole membrane	1
vacuole	1
bounding membrane of organelle	1
protein-containing complex	1
Seh1-associated complex	1
lytic vacuole	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1018 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NPRL2	DEPDC5	O75140	998
NPRL2	NPRL3	Q12980	998
NPRL2	WDR59	Q6PJI9	882
NPRL2	SEH1L	Q96EE3	866
NPRL2	SAMTOR	Q1RMZ1	849
NPRL2	WDR24	Q96S15	848
NPRL2	MIOS	Q9NXC5	827
NPRL2	RRAGA	Q7L523	776
NPRL2	RRAGC	Q9HB90	775
NPRL2	EFNA5	P52803	769
NPRL2	RRAGB	Q5VZM2	769
NPRL2	SEC13	P55735	768
NPRL2	TSC2	P49815	744
NPRL2	FLCN	Q8NFG4	717
NPRL2	RRAGD	Q9NQL2	716

IntAct

39 interactions, top by confidence:

A	B	Type	Score
NPRL3	NPRL2	psi-mi:“MI:0915”(physical association)	0.850
NPRL2	NPRL3	psi-mi:“MI:0914”(association)	0.850
NPRL2	NPRL3	psi-mi:“MI:0403”(colocalization)	0.850
NPRL2	NPRL3	psi-mi:“MI:0915”(physical association)	0.850
MIOS	SEC13	psi-mi:“MI:0914”(association)	0.790
NPRL2	DEPDC5	psi-mi:“MI:0914”(association)	0.730
ZNF414	AHCYL1	psi-mi:“MI:0914”(association)	0.640
WDR24	NPRL3	psi-mi:“MI:0914”(association)	0.600
SESN2	NPRL3	psi-mi:“MI:0914”(association)	0.530
SZT2	DEPDC5	psi-mi:“MI:0914”(association)	0.530
DEPDC5	NPRL3	psi-mi:“MI:0914”(association)	0.530
NPRL2	ZBTB5	psi-mi:“MI:0914”(association)	0.530
SAMTOR	PER1	psi-mi:“MI:0914”(association)	0.530
ITFG2	DEPDC5	psi-mi:“MI:0914”(association)	0.530
SZT2	NPRL3	psi-mi:“MI:0914”(association)	0.500
ANXA7	NPRL2	psi-mi:“MI:0915”(physical association)	0.370
NPRL2	CDKN1A	psi-mi:“MI:0915”(physical association)	0.370
DEPDC5	NPRL3	psi-mi:“MI:0914”(association)	0.350
SZT2	SEC13	psi-mi:“MI:0914”(association)	0.350
LAMP1	NPRL3	psi-mi:“MI:0403”(colocalization)	0.350
SAMTOR	MIF4GD	psi-mi:“MI:0914”(association)	0.350
ZNF414	ANKHD1	psi-mi:“MI:0914”(association)	0.350
ZNF414	CASK	psi-mi:“MI:0914”(association)	0.350
ARL5B	RAD21	psi-mi:“MI:0914”(association)	0.350
NPRL2	APAF1	psi-mi:“MI:0914”(association)	0.350

BioGRID (165): NPRL2 (Affinity Capture-RNA), NPRL2 (Affinity Capture-RNA), NPRL2 (Affinity Capture-MS), DEPDC5 (Affinity Capture-Western), NPRL3 (Affinity Capture-Western), NPRL2 (Affinity Capture-Western), WDR59 (Affinity Capture-Western), WDR24 (Affinity Capture-Western), SEH1L (Affinity Capture-Western), HERC2 (Affinity Capture-Western), RRAGA (Affinity Capture-Western), DEPDC5 (Affinity Capture-Western), NPRL2 (Affinity Capture-Western), RRAGD (Affinity Capture-Western), DEPDC5 (Affinity Capture-MS)

ESM2 similar proteins: A2VDL8, A7YWS7, O35142, O54956, O55029, O70133, O88544, O94973, O95782, P17426, P17427, P18484, P35605, P35606, P38024, P48444, P53619, P56282, Q01405, Q05AS9, Q08211, Q0VCK5, Q15436, Q15437, Q28141, Q3SZA0, Q3SZN2, Q41141, Q4R4I8, Q5E9U9, Q5F418, Q5R5G2, Q5R664, Q5R874, Q5R9P3, Q5RA77, Q5XJY5, Q5ZK03, Q5ZKQ6, Q5ZL57

Diamond homologs: O42857, Q5E9U9, Q8WTW4, Q9WUE4, Q9VXA0, P39923

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NPRL2	“form complex”	GATOR1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 29 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Amino acids regulate mTORC1	9	82.0×	1e-13
Cellular response to starvation	6	45.1×	4e-07
Cellular responses to stress	7	11.7×	9e-05
Cellular responses to stimuli	8	11.4×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of TORC1 signaling	9	104.2×	1e-14
cellular response to amino acid starvation	9	102.2×	1e-14
positive regulation of TORC1 signaling	5	52.8×	3e-06

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 1 cancer types — PANCREAS.

Clinical variants and AI predictions

ClinVar

906 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	69
Likely pathogenic	48
Uncertain significance	497
Likely benign	183
Benign	26

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1300012	NM_003995.4(NPR2):c.1444_1449del (p.Met482_Leu483del)	Pathogenic
1333664	NM_003995.4(NPR2):c.1111C>T (p.Arg371Ter)	Pathogenic
1395420	NM_003995.4(NPR2):c.507del (p.Tyr170fs)	Pathogenic
143053	NM_003995.4(NPR2):c.2647G>A (p.Val883Met)	Pathogenic
143054	NM_003995.4(NPR2):c.1963C>T (p.Arg655Cys)	Pathogenic
143055	NM_003995.4(NPR2):c.1462G>C (p.Ala488Pro)	Pathogenic
1433253	NM_003995.4(NPR2):c.2845C>T (p.Arg949Ter)	Pathogenic
1452537	NM_003995.4(NPR2):c.60del (p.Ala22fs)	Pathogenic
1453237	NM_003995.4(NPR2):c.1699G>T (p.Glu567Ter)	Pathogenic
1454887	NM_003995.4(NPR2):c.613C>T (p.Arg205Ter)	Pathogenic
1459715	NM_003995.4(NPR2):c.2221C>T (p.Arg741Ter)	Pathogenic
1459896	NM_003995.4(NPR2):c.2341C>T (p.Gln781Ter)	Pathogenic
1526377	NM_006545.5(NPRL2):c.57_58delinsC (p.Gly20fs)	Pathogenic
1678652	NM_003995.4(NPR2):c.2842dup (p.His948fs)	Pathogenic
1683471	NM_003995.4(NPR2):c.125_126insTGGCG (p.Trp42fs)	Pathogenic
1693277	NM_003995.4(NPR2):c.1579C>T (p.Leu527Phe)	Pathogenic
1695394	NM_003995.4(NPR2):c.1087C>T (p.Arg363Ter)	Pathogenic
17785	NM_003995.4(NPR2):c.343T>G (p.Trp115Gly)	Pathogenic
17786	NM_003995.4(NPR2):c.528T>A (p.Asp176Glu)	Pathogenic
17787	NM_003995.4(NPR2):c.1162C>T (p.Arg388Ter)	Pathogenic
2025379	NM_003995.4(NPR2):c.721C>T (p.Gln241Ter)	Pathogenic
2032731	NM_003995.4(NPR2):c.1511C>G (p.Ser504Ter)	Pathogenic
208357	NM_003995.4(NPR2):c.226T>C (p.Ser76Pro)	Pathogenic
2096788	NM_003995.4(NPR2):c.2424T>G (p.Tyr808Ter)	Pathogenic
2183283	NM_003995.4(NPR2):c.2965C>T (p.Arg989Ter)	Pathogenic
2194018	NM_003995.4(NPR2):c.1257G>A (p.Trp419Ter)	Pathogenic
254364	NM_006545.5(NPRL2):c.314T>C (p.Leu105Pro)	Pathogenic
254365	NM_006545.5(NPRL2):c.68_69del (p.Ile23fs)	Pathogenic
2577399	NM_003995.4(NPR2):c.1779C>A (p.Cys593Ter)	Pathogenic
2925446	NM_003995.4(NPR2):c.844C>T (p.Gln282Ter)	Pathogenic

SpliceAI

5422 predictions. Top by Δscore:

Variant	Effect	Δscore
3:50347784:G:C	donor_gain	1.0000
3:50347827:T:TA	donor_gain	1.0000
3:50347828:C:A	donor_gain	1.0000
3:50347852:T:TA	donor_gain	1.0000
3:50348406:GAGTA:G	acceptor_gain	1.0000
3:50348408:GTA:G	acceptor_gain	1.0000
3:50348409:TA:T	acceptor_gain	1.0000
3:50348410:AC:A	acceptor_loss	1.0000
3:50348411:C:CC	acceptor_gain	1.0000
3:50348411:CT:C	acceptor_loss	1.0000
3:50348562:ACCT:A	acceptor_loss	1.0000
3:50348565:T:A	acceptor_loss	1.0000
3:50348639:C:A	donor_gain	1.0000
3:50348683:A:AC	donor_gain	1.0000
3:50348684:C:CC	donor_gain	1.0000
3:50348684:CAG:C	donor_gain	1.0000
3:50348781:ATCT:A	acceptor_loss	1.0000
3:50348782:TCTG:T	acceptor_loss	1.0000
3:50348783:C:CC	acceptor_gain	1.0000
3:50348783:CTGGG:C	acceptor_loss	1.0000
3:50348784:T:A	acceptor_loss	1.0000
3:50348788:CAGAG:C	acceptor_gain	1.0000
3:50348789:A:T	acceptor_gain	1.0000
3:50348792:G:GC	acceptor_gain	1.0000
3:50348872:A:AC	donor_gain	1.0000
3:50348873:C:CC	donor_gain	1.0000
3:50348873:CTTG:C	donor_gain	1.0000
3:50348894:A:AC	donor_gain	1.0000
3:50348895:C:CC	donor_gain	1.0000
3:50349006:CTCAT:C	acceptor_gain	1.0000

AlphaMissense

2501 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:50348935:G:T	P175H	1.000
3:50349771:C:G	R78P	1.000
3:50349772:G:T	R78S	1.000
3:50349952:A:G	L50P	1.000
3:50350594:C:T	G20E	1.000
3:50350595:C:G	G20R	1.000
3:50350595:C:T	G20R	1.000
3:50350608:G:C	F15L	1.000
3:50350608:G:T	F15L	1.000
3:50350609:A:C	F15C	1.000
3:50350609:A:G	F15S	1.000
3:50350610:A:G	F15L	1.000
3:50347845:G:T	P330H	0.999
3:50347884:C:T	G317E	0.999
3:50347885:C:A	G317W	0.999
3:50347885:C:G	G317R	0.999
3:50347885:C:T	G317R	0.999
3:50348688:A:G	L227P	0.999
3:50348712:A:G	L219P	0.999
3:50348731:C:G	A213P	0.999
3:50348890:T:A	D190V	0.999
3:50348890:T:C	D190G	0.999
3:50348935:G:C	P175R	0.999
3:50349418:A:G	L139P	0.999
3:50349667:C:T	E113K	0.999
3:50349669:A:G	L112P	0.999
3:50349678:A:G	L109P	0.999
3:50349690:A:G	L105P	0.999
3:50349699:A:T	V102D	0.999
3:50349752:G:C	N84K	0.999

dbSNP variants (sampled 300 via entrez): RS1000647187 (3:50351863 G>A), RS1000658447 (3:50352209 G>A), RS1001341810 (3:50347938 C>T), RS1002851035 (3:50348417 G>A), RS1002869397 (3:50351305 A>G), RS1003207598 (3:50352750 A>ATGGGTAAGATT), RS1003446265 (3:50350340 C>A,T), RS1003793255 (3:50349651 A>G,T), RS1004904715 (3:50350744 C>A), RS1004957116 (3:50351157 G>C), RS1005923237 (3:50352350 C>T), RS1006370439 (3:50347366 C>G,T), RS1006688997 (3:50347164 T>A), RS1007416883 (3:50350676 T>C), RS1007784630 (3:50349208 C>T)

Disease associations

OMIM: gene MIM:607072 | disease phenotypes: MIM:602875, MIM:615923, MIM:616255, MIM:617116, MIM:604364, MIM:123100, MIM:616789

GenCC curated gene-disease

Disease	Classification	Inheritance
acromesomelic dysplasia 1, Maroteaux type	Definitive	Autosomal recessive
epilepsy, familial focal, with variable foci 2	Strong	Autosomal dominant
tall stature-scoliosis-macrodactyly of the great toes syndrome	Strong	Autosomal dominant
short stature with nonspecific skeletal abnormalities 1	Strong	Autosomal dominant
bone disorder	Strong	Autosomal dominant
familial focal epilepsy with variable foci	Moderate	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
focal epilepsy	Definitive	AD

Mondo (11): acromesomelic dysplasia 1, Maroteaux type (MONDO:0011275), tall stature-scoliosis-macrodactyly of the great toes syndrome (MONDO:0014401), short stature with nonspecific skeletal abnormalities 1 (MONDO:0014551), short stature with nonspecific skeletal abnormalities (MONDO:0975810), epilepsy, familial focal, with variable foci 2 (MONDO:0014924), breast ductal adenocarcinoma (MONDO:0005590), familial focal epilepsy with variable foci (MONDO:0020310), craniosynostosis (MONDO:0015469), cardiac anomalies - developmental delay - facial dysmorphism syndrome (MONDO:0014773), intellectual disability (MONDO:0001071), bone disorder (MONDO:0005381)

Orphanet (6): Tall stature-long halluces-multiple extra-epiphyses syndrome (Orphanet:329191), Acromesomelic dysplasia, Maroteaux type (Orphanet:40), Familial focal epilepsy with variable foci (Orphanet:98820), Craniosynostosis (Orphanet:1531), Developmental delay-facial dysmorphism syndrome due to MED13L deficiency (Orphanet:369891), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

29 total (29 of 29 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000708	Atypical behavior
HP:0000729	Autistic behavior
HP:0000980	Pallor
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0002069	Bilateral tonic-clonic seizure
HP:0002126	Polymicrogyria
HP:0002349	Focal aware seizure
HP:0002367	Visual hallucination
HP:0002384	Focal impaired awareness seizure
HP:0002427	Expressive aphasia
HP:0002521	Hypsarrhythmia
HP:0003401	Paresthesia
HP:0003829	Typified by incomplete penetrance
HP:0007206	Hemimegalencephaly
HP:0007359	Focal-onset seizure
HP:0008765	Auditory hallucination
HP:0010841	Multifocal epileptiform discharges
HP:0011171	Simple febrile seizure
HP:0011185	EEG with focal epileptiform discharges
HP:0012005	Deja vu aura
HP:0012469	Infantile spasms
HP:0012531	Pain
HP:0025373	Interictal EEG abnormality
HP:0031284	Flushing
HP:0031951	Nocturnal seizures
HP:0032046	Focal cortical dysplasia
HP:0100543	Cognitive impairment

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST005951_49	Body mass index	1.000000e-08
GCST006979_162	Heel bone mineral density	5.000000e-09
GCST007559_24	Sleep duration (short sleep)	3.000000e-08
GCST008839_176	Height	9.000000e-08
GCST010698_80	Subcortical volume (min-P)	3.000000e-24
GCST010699_110	Brain morphology (min-P)	4.000000e-08
GCST010701_52	Cortical surface area (MOSTest)	1.000000e-16
GCST010702_36	Subcortical volume (MOSTest)	1.000000e-10
GCST010703_262	Brain morphology (MOSTest)	2.000000e-13
GCST010703_52	Brain morphology (MOSTest)	1.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0009270	heel bone mineral density
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D001847	Bone Diseases	C05.116
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390
D003398	Craniosynostoses	C05.116.099.370.894.232; C05.660.207.240; C05.660.906.364; C16.131.621.207.240; C16.131.621.906.364
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C535661	Acromesomelic dysplasia, Maroteaux type (supp.)
C565785	Epilepsy, Partial, with Variable Foci (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cisplatin	affects expression, affects cotreatment, increases expression, decreases expression	3
Smoke	increases abundance, increases expression, decreases expression	2
lead acetate	decreases expression	1
sodium arsenite	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
jinfukang	affects cotreatment, increases expression	1
picoxystrobin	decreases expression	1
Decitabine	affects expression	1
Air Pollutants	increases abundance, increases expression	1
Amphotericin B	decreases expression	1
Cyclophosphamide	decreases expression	1
Dieldrin	increases response to substance	1
Doxorubicin	decreases expression	1
Gentamicins	decreases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Aflatoxin B1	increases methylation	1
Sodium Selenite	increases expression	1
Antirheumatic Agents	increases expression	1
Copper Sulfate	decreases expression	1

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D6LG	SDCHi003-A	Induced pluripotent stem cell	Male
CVCL_TA93	HAP1 NPRL2 (-) 1	Cancer cell line	Male
CVCL_TA94	HAP1 NPRL2 (-) 2	Cancer cell line	Male
CVCL_TA95	HAP1 NPRL2 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

228 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00722436	PHASE4	TERMINATED	Tranexamic Acid for Craniofacial Surgery
NCT02188576	PHASE4	COMPLETED	The Efficacy and Population Pharmacokinetics of Tranexamic Acid for Craniosynostosis Surgery
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT03414970	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00461344	PHASE2	TERMINATED	Docetaxel + Doxorubicin as Neoadjuvant Chemotherapy in Patients With Breast Cancer
NCT07499999	PHASE2	NOT_YET_RECRUITING	Randomized Double-Blind Phase II Trial of Baby Exemestane Versus Baby Tamoxifen in Post-Menopausal Women at High Risk for Breast Cancer
NCT02229968	PHASE2	ACTIVE_NOT_RECRUITING	Efficacy of Amicar for Children Having Craniofacial Surgery
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00912119	PHASE1	COMPLETED	Amicar Pharmacokinetics of Children Having Craniofacial Surgery
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT01166854	Not specified	RECRUITING	Characterization of Familial Myopathy and Paget Disease of Bone
NCT03527511	Not specified	COMPLETED	Effect of Active Vitamin D and Etelcalcetide on Human Osteoclasts in Patients With Chronic Kidney Disease
NCT06444503	Not specified	RECRUITING	Clinico-biological Collection of Bone, Calcium and Growth Plate Pathologies
NCT00637364	PHASE1/PHASE2	SUSPENDED	High Intensity Focused Ultrasound Tumor Treatment for Pancreatic Cancer Pain
NCT02779855	PHASE1/PHASE2	COMPLETED	Talimogene Laherparepvec in Combination With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer
NCT01753908	EARLY_PHASE1	COMPLETED	Broccoli Sprout Extract in Treating Patients With Breast Cancer
NCT01796041	EARLY_PHASE1	COMPLETED	Intraoperative Imaging of Breast Cancer With Indocyanine Green
NCT01208974	Not specified	ACTIVE_NOT_RECRUITING	Nipple-Areola Complex (NAC) Irradiation After Nipple-Sparing Mastectomy and Reconstruction
NCT01875198	Not specified	TERMINATED	Oncologic Impact of Splenectomy-omitting Radical Pancreatectomy in Well-selected Left-sided Pancreatic Cancer
NCT03543397	Not specified	UNKNOWN	MRI in Ductal Carcinoma in Situ (DCIS)
NCT03834532	Not specified	COMPLETED	Living Well After Breast Surgery
NCT00077831	Not specified	COMPLETED	Child and Infant Learning Project
NCT00106977	Not specified	COMPLETED	Clinical Study of Muenke Syndrome (FGFR3-Related Craniosynostosis)
NCT00367796	Not specified	COMPLETED	Genetic Analysis of Craniosynostosis, Philadelphia Type
NCT00769847	Not specified	WITHDRAWN	Endoscopic Treatment for Isolated, Single Suture Craniosynostosis
NCT00773643	Not specified	COMPLETED	Osteogenic Profiling of Tissue From Children With Craniosynostosis
NCT01898650	Not specified	COMPLETED	MRI for Non-invasive Evaluation of Brain Stress
NCT02287805	Not specified	COMPLETED	Qualitative and Quantitative Study Which Aims to Determine the Specifics of the Announcement for the Diagnosis of Patients With Craniosynostosis and Their Parents to Better Support Them in Their Care
NCT02561728	Not specified	WITHDRAWN	Hanger Helmet Study