NPFFR2
Chr 4neuropeptide FF receptor 2
Also known as: GPR74, HLWAR77, NPFF2, NPGPR
The protein functions as a G-protein-coupled receptor that binds neuropeptides NPAF and NPFF to regulate pain modulation and opioid system function through phosphatidylinositol-calcium signaling. Biallelic mutations cause autosomal recessive normosmic congenital hypogonadotropic hypogonadism, a disorder affecting reproductive hormone regulation that typically presents with delayed or absent puberty. The gene shows very low constraint against loss-of-function variants, consistent with recessive inheritance where one functional copy is insufficient.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly tolerant — LoF variants common in population
Tolerant to missense variation
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.
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
0 submitted variants in ClinVar
Protein Context — Lollipop Plot
NPFFR2 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools