NPFFR2

Chr 4

neuropeptide FF receptor 2

Also known as: GPR74, HLWAR77, NPFF2, NPGPR

NCBI Gene: 10886 ENSG00000056291 UniProt: Q9Y5X5 OMIM: 607449

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.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of a subfamily of G-protein-coupled neuropeptide receptors. This protein is activated by the neuropeptides A-18-amide (NPAF) and F-8-amide (NPFF) and may function in pain modulation and regulation of the opioid system. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2009]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.13

Clinical Summary— NPFFR2

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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

48 VUS of 60 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?

1.13LOEUF

pLI 0.000

Z-score 1.15

OE 0.71 (0.46–1.13)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-1.17Z-score

OE missense 1.20 (1.09–1.31)

336 obs / 281.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.71 (0.46–1.13)

0≤0.351.4

Missense OE?1.20 (1.09–1.31)

0≤0.61.4

Synonymous OE?1.20

0≤1.21.6

LoF obs/exp: 13 / 18.3Missense obs/exp: 336 / 281.0Syn Z: -1.62

This gene — mechanism propensity

0.78top 25%

GOF

0.7125th %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

60 submitted variants in ClinVar

ClinVar

Classification Summary

VUS48

Likely Benign4

Benign3

Conflicting1

VUS

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	0	0	0	0	0
VUS	0	46	2	0	48
Likely Benign	0	3	1	0	4
Benign	0	2	1	0	3
Conflicting	—				1
Total	0	51	4	0	56

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

View in ClinVar →

24 pathogenic / likely-pathogenic (of 31) ClinVar copy-number / structural variants overlap NPFFR2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →