NPBWR2

Chr 20

neuropeptides B and W receptor 2

Also known as: GPR8

NCBI Gene: 2832 ENSG00000125522 UniProt: P48146 OMIM: 600731

The encoded protein is a G protein-coupled receptor that binds neuropeptides B and W and interacts with opioid ligands, functioning in neuroendocrine regulation and food intake control. The gene is extremely intolerant to loss-of-function variants (pLI near 1.0), but no established human disease has been definitively linked to NPBWR2 mutations in current medical literature. This receptor is expressed primarily in the frontal cortex and belongs to the same structural family as opioid and somatostatin receptors.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is an integral membrane protein and G protein-coupled receptor. The encoded protein is similar in sequence to another G protein-coupled receptor (GPR7), and it is structurally similar to opioid and somatostatin receptors. This protein binds neuropeptides B and W. This gene is intronless and is expressed primarily in the frontal cortex of the brain. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.78

Clinical Summary— NPBWR2

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

57 VUS of 62 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.78LOEUF

pLI 0.000

Z-score -0.02

OE 1.01 (0.55–1.78)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.56Z-score

OE missense 0.90 (0.80–1.00)

206 obs / 230.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.01 (0.55–1.78)

0≤0.351.4

Missense OE?0.90 (0.80–1.00)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 6 / 5.9Missense obs/exp: 206 / 230.0Syn Z: 0.29

This gene — mechanism propensity

0.74top 25%

GOF

0.82top 10%

LOF

0.2485th %ile

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

GOFprediction above median

DNprediction 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

62 submitted variants in ClinVar

ClinVar

Classification Summary

VUS57

Likely Benign5

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	57	57
Likely Benign	5	5
Benign	0	0
Total	62	62

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

View in ClinVar →

36 pathogenic / likely-pathogenic (of 45) ClinVar copy-number / structural variants overlap NPBWR2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →