NRP2

Chr 2

neuropilin 2

Also known as: NP2, NPN2, PRO2714, VEGF165R2

NCBI Gene: 8828 ENSG00000118257 UniProt: Q99435

The protein functions as a transmembrane receptor that binds semaphorins and VEGF, regulating neuronal proliferation, survival, differentiation, and axon guidance through MAPK signaling pathways. Mutations cause autosomal dominant developmental disorders affecting the nervous system and potentially cardiovascular development. This gene is highly constrained against loss-of-function variants, indicating that such mutations are likely to have significant clinical consequences.

ResearchSummary from RefSeq, UniProt

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. [provided by RefSeq, Jul 2021]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.47

Clinical Summary— NRP2

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.31) despite low pLI — interpret in context.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 196 VUS of 397 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.47LOEUF

pLI 0.001

Z-score 4.47

OE 0.31 (0.20–0.47)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.18Z-score

OE missense 0.86 (0.80–0.93)

472 obs / 549.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.31 (0.20–0.47)

0≤0.351.4

Missense OE?0.86 (0.80–0.93)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 15 / 48.6Missense obs/exp: 472 / 549.9Syn Z: -0.51

This gene — mechanism propensity

0.6746th %ile

GOF

0.6639th %ile

LOF

0.3162th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

397 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1

VUS196

Likely Benign156

Benign16

Conflicting1

Likely Pathogenic

196

VUS

156

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	1	0	0	0	1
VUS	5	191	0	0	196
Likely Benign	0	24	32	100	156
Benign	2	3	1	10	16
Conflicting	—				1
Total	8	218	33	110	370

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

View in ClinVar →

26 pathogenic / likely-pathogenic (of 33) ClinVar copy-number / structural variants overlap NRP2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →