NRP2

Summary

NRP2 (neuropilin 2, HGNC:8005) is a protein-coding gene on chromosome 2q33.3, encoding Neuropilin-2 (O60462). High affinity receptor for semaphorins 3C, 3F, VEGF-165 and VEGF-145 isoforms of VEGF, and the PLGF-2 isoform of PGF.

This gene encodes a member of the neuropilin family of receptor proteins. The encoded transmembrane protein binds to SEMA3C protein {sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3C} and SEMA3F protein {sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3F}, and interacts with vascular endothelial growth factor (VEGF). This protein may play a role in cardiovascular development, axon guidance, and tumorigenesis. This protein has also been determined to act as a co-receptor for SARS-CoV-2 (which causes COVID-19) to infect host cells.

Source: NCBI Gene 8828 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 380 total — 1 pathogenic, 1 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_003872

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8005
Approved symbol	NRP2
Name	neuropilin 2
Location	2q33.3
Locus type	gene with protein product
Status	Approved
Aliases	VEGF165R2
Ensembl gene	ENSG00000118257
Ensembl biotype	protein_coding
OMIM	602070
Entrez	8828

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 7 protein_coding, 6 retained_intron, 4 protein_coding_CDS_not_defined

ENST00000272849, ENST00000357118, ENST00000357785, ENST00000360409, ENST00000412873, ENST00000417189, ENST00000450507, ENST00000460987, ENST00000464003, ENST00000467850, ENST00000468256, ENST00000472299, ENST00000477199, ENST00000478013, ENST00000478054, ENST00000483917, ENST00000485684

RefSeq mRNA: 6 — MANE Select: NM_003872 NM_003872, NM_018534, NM_201264, NM_201266, NM_201267, NM_201279

CCDS: CCDS2364, CCDS2365, CCDS46496, CCDS46497, CCDS46498, CCDS46499

Canonical transcript exons

ENST00000357785 — 17 exons

Exon	Start	End
ENSE00000796621	205716193	205716374
ENSE00000796622	205722478	205722708
ENSE00000796624	205723785	205723940
ENSE00000796626	205725913	205726082
ENSE00000796629	205727891	205728046
ENSE00000796635	205745746	205745890
ENSE00000796636	205749725	205749841
ENSE00000796640	205763674	205763936
ENSE00001238400	205743203	205743552
ENSE00001861296	205794754	205798131
ENSE00003500656	205792235	205792285
ENSE00003539835	205766783	205766803
ENSE00003552046	205697544	205697721
ENSE00003580268	205752835	205752975
ENSE00003647935	205765474	205765570
ENSE00003676480	205740519	205740663
ENSE00003906801	205682501	205683363

Expression profiles

Bgee: expression breadth ubiquitous, 238 present calls, max score 98.35.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 53.0927 / max 655.4908, expressed in 1545 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
24801	40.9139	1463
24799	10.3263	1468
24800	1.0989	632
24814	0.3065	136
24805	0.2980	144
24812	0.1006	51
24813	0.0486	22

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	98.35	gold quality
mucosa of stomach	UBERON:0001199	97.43	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.11	gold quality
lower esophagus	UBERON:0013473	97.02	gold quality
colonic epithelium	UBERON:0000397	96.91	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	96.56	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.74	gold quality
cartilage tissue	UBERON:0002418	95.34	gold quality
adrenal tissue	UBERON:0018303	94.58	gold quality
body of uterus	UBERON:0009853	94.53	gold quality
calcaneal tendon	UBERON:0003701	94.35	gold quality
smooth muscle tissue	UBERON:0001135	94.30	gold quality
nerve	UBERON:0001021	94.23	gold quality
tibial nerve	UBERON:0001323	94.23	gold quality
gall bladder	UBERON:0002110	94.18	gold quality
left ovary	UBERON:0002119	93.71	gold quality
left uterine tube	UBERON:0001303	91.16	gold quality
right ovary	UBERON:0002118	91.04	gold quality
tendon of biceps brachii	UBERON:0008188	90.33	gold quality
left adrenal gland	UBERON:0001234	90.26	gold quality
left adrenal gland cortex	UBERON:0035825	89.83	gold quality
adrenal gland	UBERON:0002369	89.81	gold quality
tendon	UBERON:0000043	89.71	gold quality
ovary	UBERON:0000992	89.54	gold quality
right adrenal gland	UBERON:0001233	89.31	gold quality
myometrium	UBERON:0001296	89.26	gold quality
sigmoid colon	UBERON:0001159	89.18	gold quality
tibia	UBERON:0000979	89.09	gold quality
stromal cell of endometrium	CL:0002255	88.95	gold quality
right adrenal gland cortex	UBERON:0035827	88.81	gold quality

Single-cell (SCXA)

Detected in 16 experiment(s), a significant marker in 14.

Experiment	Marker?	Max mean expression
E-MTAB-11268	yes	1095.69
E-GEOD-109979	yes	356.76
E-MTAB-7249	yes	280.39
E-MTAB-8142	yes	38.88
E-HCAD-10	yes	36.84
E-HCAD-1	yes	19.37
E-CURD-112	yes	15.43
E-MTAB-8410	yes	10.76
E-CURD-46	yes	9.83
E-MTAB-8498	yes	9.35
E-MTAB-9067	yes	8.47
E-GEOD-130148	yes	8.26
E-MTAB-10553	yes	6.22
E-MTAB-8271	no	894.63
E-MTAB-8205	no	381.16

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): DLX1, DLX2, EYA1, GATA2, HIF1A, LMO2, NKX2-1, NR2F2

miRNA regulators (miRDB)

175 targeting NRP2, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-7153-5P	99.94	68.89	1006

Literature-anchored findings (GeneRIF, showing 40)

• human glioma cells express class 3 semaphorins and receptors for soluble and membrane-bound semaphorins, suggesting a possible role of the semaphorin/neuropilin system in the interactions of human malignant glioma with the nervous and immune systems. (PMID:12730958)
• Np-1 and Np-2 contribute to autocrine-paracrine interactions in pancreatic cancer (PMID:14760080)
• NP-2 mRNA, in endothelium, was expressed only by the endothelium of veins, and in these cells, its expression was hormonally regulated in the converse manner: it was very low during the proliferative phase and high during the secretory phase (PMID:15613413)
• NRP2 acts as a coreceptor that enhances human endothelial cell biological responses induced by VEGF-A and VEGF-C. (PMID:16621967)
• NP2 is directly involved in an active signaling complex with the key regulators of lymphangiogenesis. (PMID:16816121)
• These results suggest that the expression of VEGFRs and NRPs on keratinocytes may constitute important regulators for its activity and may possibly be responsible for the autocrine signaling in the epidermis. (PMID:17088944)
• The polymorphisms in the NRP2 gene are associated with autism, implying that the NRP2 gene may render individuals to be predisposed to autism. (PMID:17427189)
• that neuropilin-2 (NRP-2), a receptor for the semaphorin and vascular endothelial growth factor families in neurons and endothelial cells, respectively, is expressed on the surface of human dendritic cells and is polysialylated. (PMID:17699524)
• neoplastic cells in myeloid leukemias frequently express VEGFR including NRP-1 and NRP-2 (PMID:17917967)
• Both NRP1 and NRP2 function as proangiogenic coreceptors, potentiating the activity of at least 2 proangiogenic cytokines, VEGF-A and hepatocyte grwoth factor. (PMID:18065694)
• NRP2 expression enhances cell survival, migration, invasion, and in vivo tumor growth and it may be a promising therapeutic target for colorectal cancer. (PMID:18182619)
• IL-8 might be a malignant factor in human pancreatic cancer by induction of vascular endothelial growth factor and NRP-2 expression and ERK activation. (PMID:18307536)
• hypoxia and nutrient deprivation stimulate the rapid loss of NRP1 expression in both endothelial and carcinoma cells. NRP2 expression, in contrast, is maintained under these conditions (PMID:18708346)
• In gliomas, SEMA3B, SEMA3G and NRP2 expressions were related to prolonged survival (PMID:18781179)
• Transcripts of both NRP1 and NRP2 were found to be decreased in renal biopsies from patients with diabetic nephropathy (PMID:19037249)
• Reduction of NRP-2 expression in pancreatic ductal adenocarcinoma cells decreased survival signaling, migration, invasion, and ability to grow under anchorage-independent conditions. (PMID:19088020)
• Data suggest that neuropilin 2 may increase the response to VEGF, which is more significant in gastric tumor endothelial cells (TEC) than in normal cells, leading to gastric TEC with aggressive angiogenesis phenotypes. (PMID:19409892)
• Intra-amniotic infection upregulates decidual cell vascular endothelial growth factor (VEGF) and neuropilin-1 and -2 expression: implications for infection-related preterm birth. (PMID:19474288)
• Data show that the expression of Sema3A receptors (neuropilin-1 (NRP-1), NRP-2, plexin A1, plexin A2, and plexin A3) significantly increased during M-CSF-mediated differentiation of monocytes into macrophages. (PMID:19480842)
• Neuropilin-2 in breast cancer has a role in lymph node metastasis, poor prognosis, and regulation of CXCR4 expression (PMID:19580679)
• This is the first report suggesting a differential role of NRP1 and NRP2 in renal fibrogenesis. (PMID:19736548)
• Soluble neuropilin-2 has no antirepellent activity but aggravates sympathetic nerve fiber repulsion and arthritis. Increased shedding of neuropilin-2 is probably an unfavorable sign in rheumatoid arthritis. (PMID:19790074)
• NRP2 is necessary to trigger Sema3A-induced glioma cell repulsion and attraction. (PMID:19855168)
• Polysialyted NRP2 enhances dendritic cell migration through the basic c-terminal region of CCL21. (PMID:20488940)
• BMSCs transfected with reconstructed plasmid pIRES-hBMP-2-VEGF165 could secret a high level of BMP-2 and hVEGF165. (PMID:20548225)
• Mutated soluble neuropilin-2 B domain antagonizes vascular endothelial growth factor bioactivity and inhibits tumor progression. (PMID:20651020)
• Expression of Nrp2 protein is significantly correlated with tumor progression and angiogenesis in salivary adenoid cystic carcinomas. (PMID:20851535)
• dendritic cells express the NRP2 isoforms NRP2a and NRP2b, both are susceptible to polysialylation which is required to specifically enhance chemotaxis toward CCL21 (PMID:21199821)
• A critical role of NRP2 in coordinated cell patterning and growth was confirmed using the coculture system. We conclude that NRP2 represents an important mediator of melanoma-endothelial interactions. (PMID:21324919)
• Vascular endothelial growth factor-D stimulates endothelial cell VEGF-A, stanniocalcin-1, and neuropilin-2 and has potent angiogenic effects. (PMID:21474827)
• It was concluded that hypoxia regulates VEGF and SE MA3F activities through transcriptional repression of their common receptor NRP2, providing a novel mechanism by which hypoxia induces tumor angiogenesis, growth and metastasis. (PMID:21610314)
• a direct role of NRP2 in epithelial-mesenchymal transition and highlight a cross-talk between neuropilin-2 and TGF-beta1 signaling to promote cancer progression (PMID:21747928)
• In tumoral tissue, consistently strong staining of Neuropilin-2 was noted only in renal cell carcinoma but not in any of the other tumors studied. (PMID:21840568)
• Nrp2 expression was correlated with lymph node metastasis and VEGF-D expression in papillary thyroid carcinoma. Our data also showed a role for Nrp2 in regulating VEGF-D-induced invasion and migration in vitro. (PMID:21880798)
• tumor cell-derived NRP-2 mediates critical survival signaling in gastrointestinal cancer cells (PMID:22028766)
• In the majority of lung, breast and colorectal cancers, the effects of anti-neuropilin-2 are likely to be restricted to the vasculature (PMID:22384800)
• the VEGF receptor NRP2 is induced by PTEN loss and VEGF/NRP2 signaling regulates the expression of Bmi-1, a key effector of prostate tumorigenesis induced by PTEN deletion (PMID:22777769)
• NRP2 and VEGFR-3 mRNA levels were significantly higher in some of the vascular malformations endothelial cells. (PMID:22961441)
• Inhibition of VEGF by EGCG was associated with suppression of neuropilin-2. (PMID:22971992)
• Neuropilin 2 enables the function of specific integrins that contribute to tumor initiation and progression. [review] (PMID:23076131)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	nrp2b	ENSDARG00000038446
danio_rerio	nrp2a	ENSDARG00000096546
mus_musculus	Nrp2	ENSMUSG00000025969
rattus_norvegicus	Nrp2	ENSRNOG00000031232

Paralogs (35): NRXN3 (ENSG00000021645), TLL1 (ENSG00000038295), CP (ENSG00000047457), DCBLD2 (ENSG00000057019), HEPH (ENSG00000089472), TLL2 (ENSG00000095587), NRP1 (ENSG00000099250), PCOLCE (ENSG00000106333), CNTNAP3 (ENSG00000106714), CUBN (ENSG00000107611), CNTNAP1 (ENSG00000108797), NRXN2 (ENSG00000110076), MEP1A (ENSG00000112818), CUZD1 (ENSG00000138161), MFGE8 (ENSG00000140545), MEP1B (ENSG00000141434), PDGFC (ENSG00000145431), CNTNAP4 (ENSG00000152910), CNTNAP3B (ENSG00000154529), CNTNAP5 (ENSG00000155052), CDCP2 (ENSG00000157211), PCOLCE2 (ENSG00000163710), EDIL3 (ENSG00000164176), NETO1 (ENSG00000166342), BMP1 (ENSG00000168487), PDGFD (ENSG00000170962), NETO2 (ENSG00000171208), CNTNAP2 (ENSG00000174469), NRXN1 (ENSG00000179915), HEPHL1 (ENSG00000181333), F8 (ENSG00000185010), ASTL (ENSG00000188886), F5 (ENSG00000198734), MFRP (ENSG00000235718), CNTNAP3C (ENSG00000283378)

Protein

Protein identifiers

Neuropilin-2 — O60462 (reviewed: O60462)

Alternative names: Vascular endothelial cell growth factor 165 receptor 2

All UniProt accessions (2): C9JH98, O60462

UniProt curated annotations — full annotation on UniProt →

Function. High affinity receptor for semaphorins 3C, 3F, VEGF-165 and VEGF-145 isoforms of VEGF, and the PLGF-2 isoform of PGF. (Microbial infection) Acts as a receptor for human cytomegalovirus pentamer-dependent entry in epithelial and endothelial cells.

Subunit / interactions. Heterodimer with NRP1. Binds PLXNB1. (Microbial infection) Interacts with human cytomegalovirus proteins gL, UL128, UL130 and UL131A.

Subcellular location. Membrane Secreted.

Domain organisation. The tandem CUB domains mediate binding to semaphorin, while the tandem F5/8 domains are responsible for heparin and VEGF binding.

Similarity. Belongs to the neuropilin family.

Isoforms (6)

UniProt ID	Names	Canonical?
O60462-1	A22	yes
O60462-2	A0
O60462-3	A17
O60462-4	B0
O60462-5	B5
O60462-6	s9

RefSeq proteins (6): NP_003863, NP_061004, NP_957716, NP_957718, NP_957719, NP_958436 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000421	FA58C	Domain
IPR000859	CUB_dom	Domain
IPR000998	MAM_dom	Domain
IPR008979	Galactose-bd-like_sf	Homologous_superfamily
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR014648	Neuropilin	Family
IPR022579	Neuropilin_C	Domain
IPR035914	Sperma_CUB_dom_sf	Homologous_superfamily
IPR050633	Neuropilin_MCO_CoagFactor	Family

Pfam: PF00431, PF00629, PF00754, PF11980

UniProt features (93 total): strand 43, turn 9, disulfide bond 6, helix 6, splice variant 5, domain 5, glycosylation site 4, sequence variant 4, binding site 3, region of interest 2, topological domain 2, signal peptide 1, chain 1, compositionally biased region 1, transmembrane region 1

Structure

Experimental structures (PDB)

16 structures.

PDB	Method	Resolution (Å)
6TJT	X-RAY DIFFRACTION	1.31
5DQ0	X-RAY DIFFRACTION	1.8
8IVX	X-RAY DIFFRACTION	1.9
2QQJ	X-RAY DIFFRACTION	1.95
4QDQ	X-RAY DIFFRACTION	1.95
5DN2	X-RAY DIFFRACTION	1.95
2QQO	X-RAY DIFFRACTION	2.3
4QDR	X-RAY DIFFRACTION	2.4
4QDS	X-RAY DIFFRACTION	2.4
6GH8	X-RAY DIFFRACTION	2.44
6TDB	X-RAY DIFFRACTION	2.45
2QQK	X-RAY DIFFRACTION	2.75
2QQL	X-RAY DIFFRACTION	3.1
7T4S	ELECTRON MICROSCOPY	3.1
8IVW	X-RAY DIFFRACTION	3.21
7M22	ELECTRON MICROSCOPY	3.65

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60462-F1	78.86	0.51

Antibody-complex structures (SAbDab): 5 — 2QQK, 2QQL, 7T4S, 8IVW, 8IVX

Functional residue map

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

Ligand- & substrate-binding residues (3): 197; 211; 252

Disulfide bonds (6): 28–55, 83–105, 149–175, 208–230, 277–427, 434–592

Glycosylation sites (4): 152, 157, 629, 839

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-194306	Neuropilin interactions with VEGF and VEGFR
R-HSA-447038	NrCAM interactions

MSigDB gene sets: 490 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_FOREBRAIN_NEURON_DEVELOPMENT, E2F_Q4, E2F_Q4_01, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, GOBP_VASCULAR_ENDOTHELIAL_GROWTH_FACTOR_SIGNALING_PATHWAY, GOBP_OUTFLOW_TRACT_SEPTUM_MORPHOGENESIS, GOBP_NEURON_PROJECTION_EXTENSION, MORF_MSH3, GOBP_CARDIAC_CHAMBER_MORPHOGENESIS, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_RESPONSE_TO_PEPTIDE, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_NEURON_PROJECTION_EXTENSION_INVOLVED_IN_NEURON_PROJECTION_GUIDANCE, MORF_BRCA1

GO Biological Process (32): angiogenesis (GO:0001525), positive regulation of endothelial cell proliferation (GO:0001938), outflow tract septum morphogenesis (GO:0003148), cell adhesion (GO:0007155), axon guidance (GO:0007411), positive regulation of endothelial cell migration (GO:0010595), facial nerve structural organization (GO:0021612), trigeminal nerve structural organization (GO:0021637), vestibulocochlear nerve structural organization (GO:0021649), nerve development (GO:0021675), branchiomotor neuron axon guidance (GO:0021785), gonadotrophin-releasing hormone neuronal migration to the hypothalamus (GO:0021828), ventral trunk neural crest cell migration (GO:0036486), axon extension involved in axon guidance (GO:0048846), negative chemotaxis (GO:0050919), sympathetic ganglion development (GO:0061549), trigeminal ganglion development (GO:0061551), semaphorin-plexin signaling pathway (GO:0071526), sensory neuron axon guidance (GO:0097374), sympathetic neuron projection extension (GO:0097490), sympathetic neuron projection guidance (GO:0097491), regulation of postsynapse organization (GO:0099175), neural crest cell migration involved in autonomic nervous system development (GO:1901166), facioacoustic ganglion development (GO:1903375), dorsal root ganglion morphogenesis (GO:1904835), cellular response to leukemia inhibitory factor (GO:1990830), neuron migration (GO:0001764), nervous system development (GO:0007399), heart development (GO:0007507), cell differentiation (GO:0030154), trunk neural crest cell migration (GO:0036484), vascular endothelial growth factor signaling pathway (GO:0038084)

GO Molecular Function (9): vascular endothelial growth factor receptor activity (GO:0005021), heparin binding (GO:0008201), semaphorin receptor activity (GO:0017154), growth factor binding (GO:0019838), cytokine binding (GO:0019955), signaling receptor activity (GO:0038023), identical protein binding (GO:0042802), metal ion binding (GO:0046872), protein binding (GO:0005515)

GO Cellular Component (7): semaphorin receptor complex (GO:0002116), extracellular region (GO:0005576), plasma membrane (GO:0005886), membrane (GO:0016020), axon (GO:0030424), postsynaptic membrane (GO:0045211), glutamatergic synapse (GO:0098978)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Signaling by VEGF	1
L1CAM interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cranial nerve structural organization	3
protein binding	3
axon guidance	2
cellular anatomical structure	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
endothelial cell proliferation	1
regulation of endothelial cell proliferation	1
positive regulation of epithelial cell proliferation	1
outflow tract morphogenesis	1
cardiac septum morphogenesis	1
cellular process	1
axonogenesis	1
neuron projection guidance	1
regulation of endothelial cell migration	1
positive regulation of cell migration	1
endothelial cell migration	1
facial nerve morphogenesis	1
trigeminal nerve morphogenesis	1
vestibulocochlear nerve morphogenesis	1
nervous system development	1
anatomical structure development	1
motor neuron axon guidance	1
neuron migration	1
hypothalamic tangential migration using cell-axon interactions	1
hypothalamus gonadotrophin-releasing hormone neuron development	1
trunk neural crest cell migration	1
axon extension	1
chemotaxis	1
sympathetic nervous system development	1
ganglion development	1
cranial ganglion development	1
cell surface receptor signaling pathway	1
neuron projection extension	1
transmembrane receptor protein tyrosine kinase activity	1
vascular endothelial growth factor signaling pathway	1
vascular endothelial growth factor binding	1
glycosaminoglycan binding	1
sulfur compound binding	1
transmembrane signaling receptor activity	1

Protein interactions and networks

STRING

950 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NRP2	SEMA3F	Q13275	999
NRP2	SEMA3A	Q14563	996
NRP2	VEGFC	P49767	996
NRP2	PLXNA3	P51805	993
NRP2	FLT4	P35916	992
NRP2	SEMA3C	Q99985	992
NRP2	PLXNA1	Q9UIW2	992
NRP2	PLXNA4	Q9HCM2	987
NRP2	SEMA3B	Q13214	973
NRP2	PGF	P49763	968
NRP2	KDR	P35968	942
NRP2	VEGFD	O43915	936
NRP2	SEMA6A	Q9H2E6	922
NRP2	FLT1	P16057	906
NRP2	PLXNA2	O75051	899

IntAct

61 interactions, top by confidence:

A	B	Type	Score
NRP2	Vegfc	psi-mi:“MI:0407”(direct interaction)	0.560
ST8SIA3	KLRG2	psi-mi:“MI:0914”(association)	0.530
DEFA5	NUDT19	psi-mi:“MI:0914”(association)	0.530
TSPAN11	IGLL5	psi-mi:“MI:0914”(association)	0.530
BRINP3	BUB1	psi-mi:“MI:0914”(association)	0.530
NRP2	NRP2	psi-mi:“MI:0407”(direct interaction)	0.440
NRP2	S	psi-mi:“MI:0915”(physical association)	0.400
M2	AGPS	psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
CANX	HLA-A	psi-mi:“MI:0914”(association)	0.350
ST8SIA4	FAM234B	psi-mi:“MI:0914”(association)	0.350
CSTL1	DENND11	psi-mi:“MI:0914”(association)	0.350
NAAA	POTEF	psi-mi:“MI:0914”(association)	0.350
CCL3	KRBA1	psi-mi:“MI:0914”(association)	0.350
ST14	LIPT2	psi-mi:“MI:0914”(association)	0.350
SCGB2A2	RTL8C	psi-mi:“MI:0914”(association)	0.350
NRSN1	FAM171A2	psi-mi:“MI:0914”(association)	0.350
TMEM169	GPR89A	psi-mi:“MI:0914”(association)	0.350
CEACAM8	PRRT4	psi-mi:“MI:0914”(association)	0.350
C1QA	MANBA	psi-mi:“MI:0914”(association)	0.350
TAFAZZIN	MANBA	psi-mi:“MI:0914”(association)	0.350
COL20A1	MANBA	psi-mi:“MI:0914”(association)	0.350
DEFB135	MANBA	psi-mi:“MI:0914”(association)	0.350
TRIM68	BTN3A3	psi-mi:“MI:0914”(association)	0.350
TMPRSS13	TOR1A	psi-mi:“MI:0914”(association)	0.350
OR10H2	ABCD4	psi-mi:“MI:0914”(association)	0.350
RYK	TNFRSF10B	psi-mi:“MI:0914”(association)	0.350
LYZL1	ZZEF1	psi-mi:“MI:0914”(association)	0.350

BioGRID (83): NRP2 (Affinity Capture-MS), NRP2 (Affinity Capture-MS), NRP2 (Affinity Capture-MS), NRP2 (Affinity Capture-MS), NRP2 (Affinity Capture-MS), NRP2 (Affinity Capture-MS), NRP2 (Affinity Capture-MS), NRP2 (Affinity Capture-MS), NRP2 (Affinity Capture-MS), NRP2 (Affinity Capture-MS), NRP2 (Affinity Capture-MS), NRP2 (Affinity Capture-MS), NRP2 (Affinity Capture-MS), NRP2 (Affinity Capture-MS), NRP2 (Affinity Capture-MS)

ESM2 similar proteins: A6QR11, A8WCC4, B8JK39, D3ZTD8, O15041, O35276, O35375, O42237, O57472, O60462, O70309, O75051, O95980, P13612, P18084, P23142, P26009, P26013, P57110, P70206, P70207, P70275, P80747, Q0VBD0, Q13591, Q13797, Q2VWQ2, Q5R3Z7, Q60519, Q62179, Q62217, Q62919, Q6BEA0, Q6MZW2, Q7TSK7, Q80UG2, Q86TH1, Q8CI19, Q90827, Q91009

Diamond homologs: A2RUV9, A5A6K7, O14786, O17754, O18806, O35276, O35375, O35474, O43854, O54858, O54991, O60462, O75976, O88783, O89001, P00451, P02886, P02887, P02888, P04836, P12259, P12263, P14384, P15087, P15169, P16870, P21956, P28824, P29068, P37892, P39041, P42787, P70490, P78357, P79385, P79795, P83852, P97333, P97846, P98092

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
NRP2	up-regulates	VEGFC	binding
SEMA3C	up-regulates	NRP2	binding
SEMA3F	up-regulates	NRP2	binding
VEGFC	up-regulates	NRP2	binding
SEMA3B	“up-regulates activity”	NRP2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	185
Likely benign	148
Benign	16

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
150829	GRCh38/hg38 2q33.3-34(chr2:204906843-210031449)x1	Pathogenic
521105	NM_003872.3(NRP2):c.2118del (p.Val707fs)	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

6110 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:205697639:T:A	W57R	1.000
2:205697639:T:C	W57R	1.000
2:205697641:G:C	W57C	1.000
2:205697641:G:T	W57C	1.000
2:205697679:T:C	L70P	1.000
2:205716213:G:C	R91P	1.000
2:205716254:T:A	C105S	1.000
2:205716255:G:A	C105Y	1.000
2:205716255:G:C	C105S	1.000
2:205716312:T:C	F124S	1.000
2:205716318:C:T	S126F	1.000
2:205716344:T:C	F135L	1.000
2:205716345:T:C	F135S	1.000
2:205716346:C:A	F135L	1.000
2:205716346:C:G	F135L	1.000
2:205716351:T:C	L137P	1.000
2:205722682:T:C	L213P	1.000
2:205723860:T:C	L247P	1.000
2:205723899:T:C	F260S	1.000
2:205726044:T:A	W318R	1.000
2:205726044:T:C	W318R	1.000
2:205727996:A:C	S366R	1.000
2:205727998:C:A	S366R	1.000
2:205727998:C:G	S366R	1.000
2:205697633:T:A	C55S	0.999
2:205697633:T:C	C55R	0.999
2:205697634:G:C	C55S	0.999
2:205697679:T:A	L70H	0.999
2:205697679:T:G	L70R	0.999
2:205697684:T:C	F72L	0.999

dbSNP variants (sampled 300 via entrez): RS1000014176 (2:205752934 C>G,T), RS1000070137 (2:205794601 C>A,T), RS1000087072 (2:205752623 G>A,T), RS1000101832 (2:205721917 C>T), RS1000104237 (2:205702354 T>A), RS1000202773 (2:205750779 A>C,G), RS1000223095 (2:205790242 C>T), RS1000239416 (2:205685310 TC>T), RS1000257156 (2:205705766 C>G), RS1000292658 (2:205758814 G>A,T), RS1000310955 (2:205705436 T>C), RS1000315709 (2:205734530 G>A,C), RS1000336472 (2:205734955 A>T), RS1000338591 (2:205692690 T>A), RS1000382219 (2:205777283 C>G,T)

Disease associations

OMIM: gene MIM:602070 | disease phenotypes: MIM:142623

GenCC curated gene-disease

Mondo (1): Hirschsprung disease, susceptibility to, 1 (MONDO:0007723)

Orphanet (1): Hirschsprung disease (Orphanet:388)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST002875_78	Diisocyanate-induced asthma	1.000000e-06
GCST004412_2	Craniofacial microsomia	7.000000e-10
GCST006585_2661	Blood protein levels	5.000000e-07
GCST010547_1	Neuropathy x type 2 diabetes interaction	3.000000e-08
GCST011494_17	Daytime nap	4.000000e-12

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006995	response to diisocyanate
EFO:0004149	neuropathy
EFO:0007828	daytime rest measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4295667 (SINGLE PROTEIN), CHEMBL5482995 (PROTEIN COMPLEX)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs10932125	Other	3	daunorubicin	Drug Toxicity

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs10932125	NRP2	3	2.50	1	daunorubicin

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.05	IC50	9	nM	CHEMBL5421065
8.03	IC50	9.333	nM	CHEMBL5421065
7.37	IC50	43	nM	CHEMBL5398256
6.32	IC50	475.3	nM	CHEMBL5398256

PubChem BioAssay actives

4 with measured affinity, of 6 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S)-2-[[(2S)-1-[(2S)-4-amino-2-[[(2S)-2-amino-6-[[(2S)-2-[[(2R)-2-amino-3-sulfanylpropanoyl]amino]-6-(diaminomethylideneamino)hexanoyl]amino]hexanoyl]amino]butanoyl]-2,3,3a,4,5,6,7,7a-octahydroindole-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoic acid	2016518: Inhibition of human biotinylated-VEGFA165 binding to recombinant human NRP-2 measured after 2 hrs by chemiluminescent based ELISA	ic50	0.0090	uM
(2S)-2-[[(2S)-1-[(2S)-4-amino-2-[[(2S)-6-[[(2S)-2-amino-6-(diaminomethylideneamino)hexanoyl]amino]-2-[[(2R)-2-amino-3-sulfanylpropanoyl]amino]hexanoyl]amino]butanoyl]-2,3,3a,4,5,6,7,7a-octahydroindole-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoic acid	2016518: Inhibition of human biotinylated-VEGFA165 binding to recombinant human NRP-2 measured after 2 hrs by chemiluminescent based ELISA	ic50	0.0430	uM

CTD chemical–gene interactions

70 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression	7
methylmercuric chloride	affects cotreatment, increases expression	4
sodium arsenite	affects methylation, decreases expression, increases abundance, increases expression	4
bisphenol A	increases expression, increases methylation, affects cotreatment	3
trichostatin A	affects cotreatment, increases expression	3
Arsenic	affects expression, affects methylation, increases abundance, increases expression	3
nickel sulfate	decreases expression, increases expression	2
entinostat	increases expression, affects cotreatment	2
Vorinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Cisplatin	decreases response to substance, increases expression	2
Doxorubicin	decreases expression, increases expression	2
Folic Acid	decreases expression, affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
FR900359	affects phosphorylation	1
sotorasib	decreases expression, affects cotreatment	1
dicrotophos	increases expression	1
bufotalin	decreases expression	1
sodium arsenate	decreases expression	1
titanium dioxide	decreases methylation	1
terbufos	increases methylation	1
beta-lapachone	increases expression	1
cobaltous chloride	decreases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	decreases expression	1
benzo(e)pyrene	increases methylation	1
cupric chloride	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
sphingosine 1-phosphate	decreases expression, decreases reaction	1
N-acetylsphingosine	decreases expression, decreases reaction	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4183437	Binding	Binding affinity to His6-tagged recombinant human NRP2 at 62.5 to 1000 nM treated for 60 secs by SPR method	Small Molecule Neuropilin-1 Antagonists Combine Antiangiogenic and Antitumor Activity with Immune Modulation through Reduction of Transforming Growth Factor Beta (TGFβ) Production in Regulatory T-Cells. — J Med Chem

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9LP	Ubigene HEK293 NRP2 KO	Transformed cell line	Female
CVCL_TB10	HAP1 NRP2 (-) 1	Cancer cell line	Male
CVCL_XR15	HAP1 NRP2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02343562	PHASE4	UNKNOWN	Probiotics for Prophylaxis of Postoperative Hirschsprungs Associated Enterocolitis
NCT07186647	PHASE4	COMPLETED	Laparoscopic-Assisted Transanal Pull-Through for Hirschsprung Disease in Pediatric:Short and Intermediate Outcomes of Two Different Techniques
NCT04904081	PHASE3	UNKNOWN	Feasibility of Use of Indocyanine Green in Pediatric Colorectal Surgery
NCT00630838	PHASE2	COMPLETED	Probiotic Prophylaxis of Hirschprung’s Disease Associated Enterocolitis (HAEC)
NCT01985646	EARLY_PHASE1	COMPLETED	A Trial on Conservative Treatment for Infants’ Hirschsprung Disease
NCT00478712	Not specified	RECRUITING	Hirschsprung Disease Genetic Study
NCT01515501	Not specified	COMPLETED	Endoscopic Mucosal Resection for the Diagnosis of a-Ganglionosis, a Controlled Prospective Trial (EDGE Trial)
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01927809	Not specified	UNKNOWN	Genetic Mosaicism in Hirschsprung’s Disease
NCT02193685	Not specified	UNKNOWN	Identification Genetic, Immunologic and Microbial Markers of Hirschsprung Associated Enterocolitis in Children With Hirschsprung Disease
NCT02216994	Not specified	UNKNOWN	A New Scoring System Improves Diagnostic Accuracy of Intestinal Dysganglionosis –a Prospective Study
NCT02296008	Not specified	COMPLETED	3D High Resolution Anorectal Manometry in Children After Surgery for Anorectal Disorders
NCT02776176	Not specified	UNKNOWN	Enhanced Recovery After Surgery In Hirschsprung Disease
NCT02857205	Not specified	COMPLETED	MICROPRUNG : Intestinal Microbiota Analysis in Patients With or Without Hirschsprung’s Associated EnteroColitis
NCT03269812	Not specified	UNKNOWN	Laparoscopic Assisted Pull-through Versus Other Surgical Procedures for Treatment of Hirschsprung Disease
NCT03666767	Not specified	COMPLETED	Management and Outcomes of Congenital Anomalies in Low-, Middle- and High-Income Countries
NCT04020939	Not specified	COMPLETED	The Role of Indocyanine Green Angiography Fluorescence on Intestinal Resections in Pediatric Surgery.
NCT04106947	Not specified	UNKNOWN	Transition of Care for Patients With Hirschsprung Disease and Anorectal Malformations
NCT04149093	Not specified	UNKNOWN	The Association Between Calretinin and the Function of Ganglion Cells in Hirschsprung Disease
NCT04150120	Not specified	COMPLETED	eHealth as an Aid for Facilitating and Supporting Self-management in Families With Long-term Childhood Illness
NCT04213976	Not specified	UNKNOWN	Ostomy in Continuity or Conventional Ileostomy: a Retrospective Multicentric Analysis
NCT04476225	Not specified	COMPLETED	Induced Pluripotent Stem Cells for Disease Research
NCT04598841	Not specified	COMPLETED	Nutrition Support for Hirschsprung Disease
NCT04622410	Not specified	RECRUITING	Registry for Hirschsprung Disease of the BELAPS
NCT04624334	Not specified	TERMINATED	Non-invasive Assessment of Colonic Motility
NCT04730128	Not specified	COMPLETED	Translation and Validation of a Disease-specific Questionnaire for Hirschsprung’s Disease in Danish Patients
NCT04837963	Not specified	COMPLETED	Does Hirschsprung Disease Increase the Risk of Febrile Urinary Tract Infection in Children
NCT04957667	Not specified	COMPLETED	Scintigraphic Defecography for Evaluation of Functional Outcome in an Adult Hirschsprung Population
NCT05038345	Not specified	TERMINATED	Hirschsprung Disease Trends in the United States: Analysis of the National Inpatient Sample
NCT05044741	Not specified	COMPLETED	Risk Factors of Perforated HSCR in Neonates
NCT05293353	Not specified	UNKNOWN	Neokare Safety and Tolerability Assessment in Neonates With GI Problems
NCT05307419	Not specified	UNKNOWN	Full Thickness vs. Rectal Suction Biopsy in the Diagnosis of Hirschsprungs Disease
NCT05450991	Not specified	RECRUITING	Long-term Qualitative and Quantitative Outcomes of Children With Hirschsprung’s Disease and Anorectal Malformations
NCT05655845	Not specified	UNKNOWN	Risk Factors for Bowel Dysfunction at Preschool and Early Childhood Age in Children With Hirschsprung Disease
NCT06072976	Not specified	RECRUITING	The Influence of Feeding Source on the Gut Microbiome and Time to Full Feeds in Neonates With Congenital Gastrointestinal Pathologies
NCT06197061	Not specified	UNKNOWN	Comparison of Robot-assisted With Laparoscopic-assisted Modified Soave Procedure for Classical Hirschsprung Disease
NCT06573723	Not specified	RECRUITING	Institutional Registry of Rare Diseases
NCT06590142	Not specified	RECRUITING	Hirschsprung’s Advances; Working Towards Autologous tIssue therapIes
NCT06592534	Not specified	NOT_YET_RECRUITING	Babies With Enterocolitis - A Study of Faecal Calprotectin in Hirschsprung Disease (The BEACH Study)
NCT06650683	Not specified	RECRUITING	Impact of Providing Nursing Support on Parental Stress Related to Preoperative Care of a Newborn with Hirschsprung’s Disease