PROKR2

Summary

PROKR2 (prokineticin receptor 2, HGNC:15836) is a protein-coding gene on chromosome 20p12.3, encoding Prokineticin receptor 2 (Q8NFJ6). Receptor for prokineticin 2.

Prokineticins are secreted proteins that can promote angiogenesis and induce strong gastrointestinal smooth muscle contraction. The protein encoded by this gene is an integral membrane protein and G protein-coupled receptor for prokineticins. The encoded protein is similar in sequence to GPR73, another G protein-coupled receptor for prokineticins.

Source: NCBI Gene 128674 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypogonadotropic hypogonadism 3 with or without anosmia (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 253 total — 6 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 115
• Druggable target: yes
• MANE Select transcript: NM_144773

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15836
Approved symbol	PROKR2
Name	prokineticin receptor 2
Location	20p12.3
Locus type	gene with protein product
Status	Approved
Aliases	GPR73b, PKR2, GPRg2, dJ680N4.3
Ensembl gene	ENSG00000101292
Ensembl biotype	protein_coding
OMIM	607123
Entrez	128674

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000217270, ENST00000678059, ENST00000678254

RefSeq mRNA: 1 — MANE Select: NM_144773 NM_144773

CCDS: CCDS13089

Canonical transcript exons

ENST00000678254 — 3 exons

Exon	Start	End
ENSE00000658178	5313912	5314377
ENSE00003905609	5316494	5316954
ENSE00003907645	5299218	5302736

Expression profiles

Bgee: expression breadth broad, 32 present calls, max score 72.91.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0706 / max 24.2171, expressed in 20 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
186294	0.0706	20

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	72.91	gold quality
ganglionic eminence	UBERON:0004023	71.78	gold quality
ventricular zone	UBERON:0003053	61.89	gold quality
prefrontal cortex	UBERON:0000451	59.37	gold quality
Brodmann (1909) area 9	UBERON:0013540	56.24	gold quality
upper leg skin	UBERON:0004262	54.51	silver quality
bone marrow cell	CL:0002092	54.20	gold quality
neocortex	UBERON:0001950	52.60	gold quality
frontal cortex	UBERON:0001870	52.57	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	52.38	gold quality
anterior cingulate cortex	UBERON:0009835	52.19	gold quality
cerebral cortex	UBERON:0000956	50.17	gold quality
skin of hip	UBERON:0001554	49.27	silver quality
lymph node	UBERON:0000029	49.22	gold quality
right frontal lobe	UBERON:0002810	47.79	gold quality
bone marrow	UBERON:0002371	47.44	silver quality
colonic epithelium	UBERON:0000397	45.80	gold quality
hindlimb stylopod muscle	UBERON:0004252	44.73	gold quality
Ammon’s horn	UBERON:0001954	44.60	gold quality
superior frontal gyrus	UBERON:0002661	43.61	gold quality
blood	UBERON:0000178	43.45	silver quality
forebrain	UBERON:0001890	43.38	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
secondary oocyte	CL:0000655	42.57	gold quality
sural nerve	UBERON:0015488	42.48	gold quality
skeletal muscle tissue	UBERON:0001134	42.20	gold quality
amygdala	UBERON:0001876	41.78	gold quality
tonsil	UBERON:0002372	41.73	gold quality
brain	UBERON:0000955	41.64	gold quality
middle temporal gyrus	UBERON:0002771	41.63	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.14

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

32 targeting PROKR2, 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-MIR-4425	100.00	67.59	1049
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-1976	99.74	65.48	1127
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-567	99.63	68.57	1219
HSA-MIR-6513-3P	99.59	69.77	1102
HSA-MIR-516B-5P	99.56	66.33	1495
HSA-MIR-216A-5P	99.50	68.02	1288
HSA-MIR-297	99.40	69.58	1418
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-6504-3P	99.17	69.31	2891
HSA-MIR-10399-5P	99.17	69.87	2610
HSA-MIR-4426	99.17	66.74	1949
HSA-MIR-7151-3P	99.04	69.72	2370
HSA-MIR-4324	99.04	70.14	1569
HSA-MIR-455-3P	98.94	67.68	878
HSA-MIR-3074-5P	98.82	66.56	1414
HSA-MIR-3149	98.77	67.13	1639
HSA-MIR-513B-3P	98.76	68.12	1577
HSA-MIR-508-3P	98.66	69.62	887
HSA-MIR-9500	98.62	66.54	1845
HSA-MIR-619-5P	98.57	64.97	1988
HSA-MIR-5089-5P	98.45	66.06	1388
HSA-MIR-6773-3P	98.17	65.51	1213
HSA-MIR-6736-3P	96.98	65.22	1342
HSA-MIR-339-5P	96.73	66.01	820
HSA-MIR-3654	96.43	66.55	646

Literature-anchored findings (GeneRIF, showing 40)

• molecular cloning, amino acid sequence and expression in several human tissues (PMID:12427552)
• Paracrine role for the PKs and their receptors in endometrial vascular function. (PMID:15126578)
• study demonstrated that prokineticin 1 and 2 and their receptors are expressed in human prostate and that their levels increased with prostate malignancy (PMID:16763065)
• These findings reveal that insufficient prokineticin-signaling through PROKR2 leads to abnormal development of the olfactory system and reproductive axis in man. (PMID:17054399)
• Loss-of-function mutations in PROK2 and PROKR2 underlie both Kallmann syndrome (KS) and normosmic idiopathic hypogonadotropic hypogonadism (IHH). (PMID:18559922)
• Loss-of-function mutations in the genes encoding prokineticin-2 or prokineticin receptor-2 cause autosomal recessive Kallmann syndrome. (PMID:18682503)
• Two Kallmann syndrome patients presented a heterozygous T-to-G transversion in exon 2 (c.518T>G). (PMID:18723471)
• In Kallmann syndrome patients, ten different missense mutations have been identified in PROKR2. (PMID:18826963)
• Results suggest that PROKR2 may play a role in the pathophysiology of mood disorders in the Japanese population. (PMID:19544013)
• Male patients carrying biallelic mutations in PROK2 or PROKR2 have a less variable and on average a more severe reproductive phenotype than patients carrying monoallelic mutations in these genes. (PMID:20022991)
• The functional characteristics of coronary endothelial cells depend on the expression of PKR1 and PKR2 levels and the divergent signaling pathways used by these receptors. (PMID:20023120)
• Patients with this genetic form of Kallmann syndrome have been reported to have a possible increased prevalence of obesity and sleep disorders, which may be related to the role of PROKR2 in food intake and circadian rhythms (Review) (PMID:20389090)
• PROKR2 may play a role in the pathophysiology of methamphetamine dependence in the Japanese population. (PMID:20576534)
• one tag SNP of PKR2 (rs6053283) was significantly associated with idiopathic recurrent pregnancy loss. (PMID:20847187)
• ligation of tubal TLR2 and activation of NFkappaB by C. trachomatis leads to increased tubal PROKR2, thereby predisposing the tubal microenvironment to ectopic implantation. (PMID:21224062)
• positive charges in the second intracellular loop mutations of the PKR2 receptor have roles in G-protein coupling and receptor trafficking (PMID:21454486)
• Findings, together with the detection of sequence variants in PROKR1, PROK1 and PROKR2 genes associated to HSCR and, in some cases in combination with RET or GDNF mutations, provide evidence to consider them as susceptibility genes for HSCR. (PMID:21858136)
• The results suggest an identical transmembrane-bundle binding site for hPKR1 and hPKR2. (PMID:22132188)
• hCG increases EG-VEGF, PROKR1 and PROKR2 mRNA and protein expression in a dose- and time-dependent manner, demonstrating a new role for hCG in the regulation of EG-VEGF and its receptors (PMID:22138749)
• genetic association studies in 103 patients from US and UK: Mutations in PROKR2, FGFR1, or FGF8 contributed to 7.8% of patients with combined pituitary hormone deficiency or septo-optic dysplasia. Data suggest genetic overlap with Kallmann syndrome. (PMID:22319038)
• We report PROKR2 variants in congenital hypopituitarism with pituitary stalk interruption, suggesting a potential role of the prokineticin pathway in pituitary development. (PMID:22466334)
• The R80C mutant of PROKR2 exerts a dominant negative effect on wild type PROKR2 by interfering with wild type receptor expression. (PMID:22745195)
• An ancient founder missense mutation in PROKR2 impairs human reproduction. (PMID:22773735)
• Three PROKR2 mutations previously described in Kallmann syndrome and one new PROK2 mutation were found in patients with isolated congenital anosmia. (PMID:23082007)
• PROKR2 signaling does not directly affect Sertoli cell function in autosomal recessive Kallmann syndrome. (PMID:23200691)
• The role of PROKR2 in the etiology of congenital hypopituitarism, septo-optic dysplasia, and Kallmann syndrome is uncertain. (PMID:23386640)
• V331M variant confers lower risk for recurrent miscarriage (PMID:23687280)
• Prokineticin (PK)1/PKR2-signalling pathway is involved in the regulation of the functional adequate capillarization in late pregnancy (PMID:23891065)
• the distal region of the IL3 region of PROKR2 may differentially influence receptor trafficking and G-protein coupling (PMID:23969157)
• An unexpectedly large prevalence of PROKR2 mutations was found in Kallmann syndrome patients from the Maghreb. (PMID:24031091)
• Single PROKR2 missense allelic variants can either affect both cAMP and IP signaling pathways differently or selectively. (PMID:24276467)
• TSHZ1 is a key regulator of mammalian olfactory bulb development and function and controls the expression of PROKR2. (PMID:24487590)
• PK2-induced PKR2 endocytosis is GRK2- and clathrin-dependent, but beta-arrestin-independent. (PMID:24509228)
• Wild-type PROKR2 activates different G-protein subtypes (Gq, Gs, and Gi/o) and recruits beta-arrestins. The effects of 9 missense mutations on these 2 processes showed that some mutations affected both or only one of them. (PMID:24830383)
• Study corroborates the clinical relevance of the EG-VEGF system in human early pregnancy, and provides evidence for the gene-gene interactions of EG-VEGF and PROKR variants. (PMID:25064403)
• PKR2 protomers form type II dimers involving TMs 4 and 5, with a role for TM5 in modulation of PKR2 function. (PMID:25449422)
• EG-VEGF, BV8, and PROKR2 gene expression is approximately five, four, and two times higher in cystic fibrosis lungs compared with controls. (PMID:26047640)
• PROKR2 expression in human fetal ovary remained unchanged throughout gestation. (PMID:26192875)
• Data suggest that prokineticins (PROK1 and PROK2) and prokineticin receptors (PROKR1 and PROKR2) act as main regulators of physiological functions of ovary, uterus, placenta, and testis. [REVIEW] (PMID:26574895)
• PROKR2 may play a role in susceptibility of pituitary stalk interruption syndrome (PMID:26956854)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Prokr2	ENSMUSG00000050558
rattus_norvegicus	Prokr2	ENSRNOG00000082181

Paralogs (33): TACR2 (ENSG00000075073), GPR50 (ENSG00000102195), TACR1 (ENSG00000115353), GPR75 (ENSG00000119737), PRLHR (ENSG00000119973), GPR83 (ENSG00000123901), MCHR1 (ENSG00000128285), OR11H1 (ENSG00000130538), MTNR1B (ENSG00000134640), MCHR2 (ENSG00000152034), NPY1R (ENSG00000164128), NPY5R (ENSG00000164129), MTNR1A (ENSG00000168412), PROKR1 (ENSG00000169618), TACR3 (ENSG00000169836), OR9G1 (ENSG00000174914), OR11H4 (ENSG00000176198), OR11H6 (ENSG00000176219), OR9A2 (ENSG00000179468), GPR88 (ENSG00000181656), GPR19 (ENSG00000183150), NPY2R (ENSG00000185149), OR11G2 (ENSG00000196832), NPY4R (ENSG00000204174), OR11A1 (ENSG00000204694), OR9A1P (ENSG00000237621), OR11H12 (ENSG00000257115), OR9A4 (ENSG00000258083), OR11H2 (ENSG00000258453), OR11H7 (ENSG00000258806), NPY4R2 (ENSG00000264717), OR10X1 (ENSG00000279111), OR51F1 (ENSG00000280021)

Protein

Protein identifiers

Prokineticin receptor 2 — Q8NFJ6 (reviewed: Q8NFJ6)

Alternative names: G-protein coupled receptor 73-like 1, G-protein coupled receptor I5E, GPR73b, GPRg2

All UniProt accessions (2): Q8NFJ6, A0A7I2V3D2

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for prokineticin 2. Exclusively coupled to the G(q) subclass of heteromeric G proteins. Activation leads to mobilization of calcium, stimulation of phosphoinositide turnover and activation of p44/p42 mitogen-activated protein kinase.

Subunit / interactions. Homodimer.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in the ileocecum, thyroid gland, pituitary gland, salivary gland, adrenal gland, testis, ovary and brain.

Disease relevance. Hypogonadotropic hypogonadism 3 with or without anosmia (HH3) [MIM:244200] A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. In some cases, it is associated with non-reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH). The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. The genetics of hypogonadotropic hypogonadism involves various modes of transmission. Oligogenic inheritance has been reported in some patients carrying mutations in PROKR2 as well as in other HH-associated genes including KAL1, SEMA3A, PROK2, GNRH1 and FGFR1.

Similarity. Belongs to the G-protein coupled receptor 1 family.

RefSeq proteins (1): NP_658986* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR000611	NPY_rcpt	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain

Pfam: PF00001

UniProt features (38 total): sequence variant 19, topological domain 8, transmembrane region 7, glycosylation site 2, chain 1, disulfide bond 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NFJ6-F1	78.50	0.50

Functional residue map

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

Disulfide bonds (1): 128–208

Glycosylation sites (2): 7, 27

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-375276	Peptide ligand-binding receptors
R-HSA-416476	G alpha (q) signalling events

MSigDB gene sets: 265 (showing top): GOBP_CIRCADIAN_RHYTHM, REACTOME_PEPTIDE_LIGAND_BINDING_RECEPTORS, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, OCT1_06, GOBP_RESPONSE_TO_HORMONE, GOMF_PEPTIDE_RECEPTOR_ACTIVITY, OCT1_B, YATGNWAAT_OCT_C, REACTOME_CLASS_A_1_RHODOPSIN_LIKE_RECEPTORS, REACTOME_G_ALPHA_Q_SIGNALLING_EVENTS, GOMF_TRANSMEMBRANE_SIGNALING_RECEPTOR_ACTIVITY, GOBP_RHYTHMIC_PROCESS, GOMF_G_PROTEIN_COUPLED_RECEPTOR_ACTIVITY, MEISSNER_BRAIN_HCP_WITH_H3K4ME3_AND_H3K27ME3, MEISSNER_NPC_HCP_WITH_H3K4ME2_AND_H3K27ME3

GO Biological Process (5): G protein-coupled receptor signaling pathway (GO:0007186), circadian rhythm (GO:0007623), cellular response to hormone stimulus (GO:0032870), signal transduction (GO:0007165), neuropeptide signaling pathway (GO:0007218)

GO Molecular Function (3): G protein-coupled receptor activity (GO:0004930), neuropeptide Y receptor activity (GO:0004983), protein binding (GO:0005515)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Class A/1 (Rhodopsin-like receptors)	1
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
G protein-coupled receptor signaling pathway	2
G protein-coupled receptor activity	1
signal transduction	1
rhythmic process	1
response to hormone	1
cellular response to chemical stimulus	1
cellular response to endogenous stimulus	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
transmembrane signaling receptor activity	1
neuropeptide receptor activity	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

820 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PROKR2	PROK2	Q9HC23	999
PROKR2	PROK1	P58294	994
PROKR2	ANOS1	P23352	976
PROKR2	GNRH1	P01148	878
PROKR2	CHD7	Q9P2D1	857
PROKR2	FGFR1	P11362	817
PROKR2	ADCY3	O60266	755
PROKR2	NSMF	Q6X4W1	738
PROKR2	HS6ST1	O60243	724
PROKR2	TAC3	Q9UHF0	720
PROKR2	HESX1	Q9UBX0	699
PROKR2	ALDH18A1	P54886	665
PROKR2	LHX4	Q969G2	656
PROKR2	ESX1	Q8N693	647
PROKR2	KISS1	Q15726	642

IntAct

16 interactions, top by confidence:

A	B	Type	Score
PROKR2	UBE2J1	psi-mi:“MI:0915”(physical association)	0.560
IGFBP5	PROKR2	psi-mi:“MI:0915”(physical association)	0.560
ADIPOQ	PROKR2	psi-mi:“MI:0915”(physical association)	0.560
GJA8	PROKR2	psi-mi:“MI:0915”(physical association)	0.560
PROKR2	FNDC9	psi-mi:“MI:0915”(physical association)	0.560
UBE2J1	PROKR2	psi-mi:“MI:0915”(physical association)	0.000
IGFBP5	PROKR2	psi-mi:“MI:0915”(physical association)	0.000
ADIPOQ	PROKR2	psi-mi:“MI:0915”(physical association)	0.000
PROKR2	GJA8	psi-mi:“MI:0915”(physical association)	0.000
PROKR2	FNDC9	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (8): IGFBP5 (Two-hybrid), GJA8 (Two-hybrid), FNDC9 (Two-hybrid), ADIPOQ (Two-hybrid), UBE2J1 (Two-hybrid), PROKR2 (Positive Genetic), PROKR2 (Affinity Capture-Western), PROKR2 (Two-hybrid)

ESM2 similar proteins: O02813, O02835, O02836, O43614, O62809, O93603, P0C0L6, P0DQD5, P21555, P21761, P25929, P28647, P30731, P34981, P34992, P35382, P47751, P49146, P50391, P56719, P58308, P70031, P79113, P79217, P79945, P97295, Q04573, Q1RMU8, Q28596, Q56H79, Q5IS62, Q61041, Q61212, Q61618, Q63447, Q6W5P4, Q8BZP8, Q8K458, Q8NFJ6, Q8SPN1

Diamond homologs: A0A287A2K5, C8YUV0, O00155, O02836, O08786, O15973, O18935, O19012, O19014, O19025, O19032, O19054, O19091, O62729, O77408, O77700, O77721, O77830, O97665, O97772, P04761, P08482, P0C5I1, P11229, P12657, P17200, P18089, P19328, P22270, P25021, P30545, P30551, P30552, P30553, P30796, P32211, P32238, P32239, P32302, P46627

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PROK2	up-regulates	PROKR2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	8
Uncertain significance	142
Likely benign	47
Benign	19

Top pathogenic / likely-pathogenic (14)

Variant ID	HGVS	Classification
2637789	NC_000020.10:g.(?5279863)(5283383_5294557)del	Pathogenic
2722190	NM_144773.4(PROKR2):c.100_104del (p.Asp34fs)	Pathogenic
279994	NM_144773.4(PROKR2):c.458+1G>A	Pathogenic
2987105	NM_144773.4(PROKR2):c.390del (p.Val131fs)	Pathogenic
3453	NM_144773.4(PROKR2):c.969G>A (p.Met323Ile)	Pathogenic
4536631	PROKR2, TRP212TER	Pathogenic
1184527	NM_144773.4(PROKR2):c.491G>A (p.Arg164Gln)	Likely pathogenic
1324963	NM_144773.4(PROKR2):c.691G>A (p.Glu231Lys)	Likely pathogenic
2432848	NM_144773.4(PROKR2):c.201C>A (p.Cys67Ter)	Likely pathogenic
2579639	NM_144773.4(PROKR2):c.948C>G (p.Tyr316Ter)	Likely pathogenic
267202	NM_144773.4(PROKR2):c.97T>C (p.Tyr33His)	Likely pathogenic
3587501	NM_144773.4(PROKR2):c.1010dup (p.Asn338fs)	Likely pathogenic
3587525	NM_144773.4(PROKR2):c.324del (p.Phe109fs)	Likely pathogenic
4077446	NM_144773.4(PROKR2):c.896A>T (p.Asp299Val)	Likely pathogenic

SpliceAI

237 predictions. Top by Δscore:

Variant	Effect	Δscore
20:5313907:CTCA:C	donor_loss	1.0000
20:5313911:C:A	donor_loss	1.0000
20:5313911:CCTGT:C	donor_gain	1.0000
20:5302733:ATATC:A	acceptor_loss	0.9900
20:5302734:TAT:T	acceptor_gain	0.9900
20:5302734:TATCT:T	acceptor_loss	0.9900
20:5302735:ATCT:A	acceptor_loss	0.9900
20:5302736:TC:T	acceptor_loss	0.9900
20:5302737:C:CC	acceptor_gain	0.9900
20:5302737:CTG:C	acceptor_loss	0.9900
20:5302738:T:C	acceptor_loss	0.9900
20:5307045:TGAA:T	donor_gain	0.9900
20:5313910:A:AC	donor_gain	0.9900
20:5313911:C:CC	donor_gain	0.9900
20:5302732:GATAT:G	acceptor_gain	0.9800
20:5302735:AT:A	acceptor_gain	0.9800
20:5302733:ATAT:A	acceptor_gain	0.9700
20:5302740:G:GC	acceptor_gain	0.9600
20:5312746:A:C	donor_gain	0.9100
20:5313910:AC:A	donor_gain	0.9100
20:5313911:CC:C	donor_gain	0.9100
20:5313911:CCT:C	donor_gain	0.9100
20:5304746:G:C	donor_gain	0.8900
20:5302756:A:T	acceptor_gain	0.8800
20:5313909:CACCT:C	donor_gain	0.8800
20:5303967:G:GC	acceptor_gain	0.8700
20:5307055:T:C	donor_gain	0.8700
20:5302740:G:C	acceptor_gain	0.8200
20:5313908:TCA:T	donor_gain	0.8200
20:5307044:CTGA:C	donor_gain	0.8100

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000228848 (20:5316811 G>A), RS1000241428 (20:5306487 T>G), RS1000345354 (20:5312926 G>A), RS1000414736 (20:5307359 A>G,T), RS1000430808 (20:5311438 G>A), RS1000654293 (20:5306233 A>T), RS1000662086 (20:5301460 A>T), RS1001187970 (20:5317850 T>C), RS1001307596 (20:5301465 A>G), RS1001379361 (20:5301758 A>G), RS1001496163 (20:5318141 A>G,T), RS1001585144 (20:5306980 T>C,G), RS1001678464 (20:5317731 T>G), RS1001899551 (20:5307548 T>C), RS1002037363 (20:5306692 G>A,T)

Disease associations

OMIM: gene MIM:607123 | disease phenotypes: MIM:244200, MIM:146110, MIM:147950

GenCC curated gene-disease

Disease	Classification	Inheritance
hypogonadotropic hypogonadism 3 with or without anosmia	Definitive	Autosomal dominant
septooptic dysplasia	Supportive	Autosomal dominant
hypogonadotropic hypogonadism	Supportive	Autosomal dominant
Kallmann syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
hypogonadotropic hypogonadism 3 with or without anosmia	Definitive	AD

Mondo (9): hypogonadotropic hypogonadism 3 with or without anosmia (MONDO:0009482), amenorrhea (MONDO:0001836), hypogonadotropic hypogonadism 7 with or without anosmia (MONDO:0007794), infertility disorder (MONDO:0005047), hypogonadotropic hypogonadism (MONDO:0018555), Kallmann syndrome (MONDO:0018800), hypogonadotropic hypogonadism 2 with or without anosmia (MONDO:0007844), neurodevelopmental disorder (MONDO:0700092), septooptic dysplasia (MONDO:0008428)

Orphanet (4): Kallmann syndrome (Orphanet:478), Male infertility with azoospermia or oligozoospermia due to single gene mutation (Orphanet:399805), Normosmic congenital hypogonadotropic hypogonadism (Orphanet:432), Male infertility with spermatogenesis disorder (Orphanet:399775)

HPO phenotypes

115 total (30 of 115 shown, HPO-id order):

HPO	Term
HP:0000002	Abnormality of body height
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000008	Abnormal morphology of female internal genitalia
HP:0000013	Hypoplasia of the uterus
HP:0000026	Male hypogonadism
HP:0000027	Azoospermia
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000054	Micropenis
HP:0000104	Renal agenesis
HP:0000118	Phenotypic abnormality
HP:0000122	Unilateral renal agenesis
HP:0000134	Female hypogonadism
HP:0000144	Decreased fertility
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000204	Cleft upper lip
HP:0000316	Hypertelorism
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000458	Anosmia
HP:0000486	Strabismus
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000551	Color vision defect
HP:0000601	Hypotelorism
HP:0000609	Optic nerve hypoplasia
HP:0000639	Nystagmus
HP:0000716	Depression

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009856_41	Leukocyte telomere length	5.000000e-06

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D000568	Amenorrhea	C23.550.568.500
D007246	Infertility	C12.100.750
D017436	Kallmann Syndrome	C12.050.351.875.253.096.750; C12.200.706.316.096.750; C12.800.316.096.750; C16.131.939.316.096.750; C16.320.467; C19.391.119.096.750; C19.391.482.600
D065886	Neurodevelopmental Disorders	F03.625
D025962	Septo-Optic Dysplasia	C10.292.562.700.375.875; C10.500.034.937; C10.500.760.500; C11.590.436.400.875; C16.131.666.034.937; C16.131.666.763.500
C562785	Idiopathic Hypogonadotropic Hypogonadism (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5548 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: gpcr — Prokineticin receptors

Most potent curated ligand interactions (8 total), top 8:

Ligand	Action	Affinity	Parameter
MIT1	Full agonist	9.2	pIC50
[125I]BH-MIT1	Agonist	9.17	pIC50
prokineticin-2	Full agonist	8.2	pIC50
PKR-A	Antagonist	7.36	pIC50
prokineticin-1	Full agonist	7.3	pIC50
prokineticin-2β	Full agonist	6.0	pIC50
triazine compound PC10	Antagonist	5.92	pIC50
triazine compound PC1	Antagonist	5.79	pKi

Binding affinities (BindingDB)

8 measured of 8 human assays (8 total across all organisms); most potent 8 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(-)-(2R)-1-(benzimidazol-4- ylmethyl)-N-(9-chloro-3,4- dihydro-2H-1,5- benzodioxepin-7-ylmethyl)-N- isobutylpiperidine-2- carboxamide	KI	1.3 nM	US-10780095: Compositions and methods for treating disorders of circadian and diurnal rhythms using prokineticin 2 agonists and antagonists
(-)-(3R)-1-(benzimidazol-4- ylmethyl)-N-(9-chloro-3,4- dihydro-2H-1,5- benzodioxepin-7-ylmethyl)-N- isobutylpyrrolidine-3- carboxamide	KI	1.7 nM	US-10780095: Compositions and methods for treating disorders of circadian and diurnal rhythms using prokineticin 2 agonists and antagonists
(+-)-2-Methyl-3-(benzimidazol- 4-ylmethylamino)-N-(9- chloro-3,4-dihydro-2H-1,5- benzodioxepin-7-ylmethyl)-N- isobutylpropanamide	KI	2.1 nM	US-10780095: Compositions and methods for treating disorders of circadian and diurnal rhythms using prokineticin 2 agonists and antagonists
(-)-(3R)-1-(benzimidazol-4- ylmethyl)-N-(9-chloro-3,4- dihydro-2H-1,5- benzodioxepin-7-ylmethyl)-N- isobutylpiperidine-3- carboxamide	KI	3 nM	US-10780095: Compositions and methods for treating disorders of circadian and diurnal rhythms using prokineticin 2 agonists and antagonists
3-[2-({5-[(4-ethylphenyl)methyl]-1-[(4-methoxyphenyl)methyl]-4,6-dioxo-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl}amino)ethyl]guanidine	KI	22 nM
A457	IC50	102 nM
6-[(2-aminoethyl)amino]-3-[(4-ethylphenyl)methyl]-1-[(4-methoxyphenyl)methyl]-1,2,3,4-tetrahydro-1,3,5-triazine-2,4-dione	KI	440 nM
6-{[2-(4,5-dihydro-1H-imidazol-2-ylamino)ethyl]amino}-3-[(4-ethylphenyl)methyl]-1-[(4-methoxyphenyl)methyl]-1,2,3,4-tetrahydro-1,3,5-triazine-2,4-dione	KI	4720 nM

ChEMBL bioactivities

6 potent at pChembl≥5 of 8 total, top 6 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.89	Ki	1.3	nM	CHEMBL5775045
8.77	Ki	1.7	nM	CHEMBL5978988
8.72	Ki	1.9	nM	CHEMBL5958161
8.68	Ki	2.1	nM	CHEMBL5966175
8.52	Ki	3	nM	CHEMBL5861319
5.79	Ki	1610	nM	CHEMBL457515

PubChem BioAssay actives

3 with measured affinity, of 15 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
1-benzyl-N-[(6-chloro-3,4-dihydro-2H-1,5-benzodioxepin-8-yl)methyl]-N-(2-methylpropyl)pyrrolidine-3-carboxamide	1802836: Calcium Mobilization Assay from Article 10.1074/jbc.M114.556381: “Functional rescue of Kallmann syndrome-associated prokineticin receptor 2 (PKR2) mutants deficient in trafficking.”	ic50	0.1020	uM
2-[2-[[5-[(4-ethylphenyl)methyl]-1-[(4-methoxyphenyl)methyl]-4,6-dioxo-1,3,5-triazin-2-yl]amino]ethyl]guanidine	1798670: Receptor Binding Assay from Article 10.1021/jm800854e: “Triazine Compounds as Antagonists at Bv8-Prokineticin Receptors.”	ki	1.6100	uM

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Resveratrol	affects cotreatment, decreases expression	2
arsenite	increases methylation	1
sodium arsenite	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases expression, affects response to substance, increases expression	1
CGP 52608	affects binding, increases reaction	1
nutlin 3	increases expression, affects cotreatment	1
Benzo(a)pyrene	affects methylation	1
Copper	affects cotreatment, decreases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Diazinon	increases methylation	1
Folic Acid	decreases expression	1
Lipopolysaccharides	affects response to substance, increases expression	1
Methamphetamine	affects response to substance	1
Plant Extracts	affects cotreatment, decreases expression	1
Valproic Acid	increases methylation	1
Sodium Selenite	decreases expression	1

ChEMBL screening assays

9 unique, capped per target: 5 functional, 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4883575	Binding	PRESTO-Tango GPCRome screening (PK2)	Data for DCP probe UCSF924
CHEMBL998632	Functional	Antagonist activity at PKR2 expressed in CHO cell membrane assessed as reduction of Bv8-induced increase in intracellular calcium level at 100 nM	Triazine compounds as antagonists at Bv8-prokineticin receptors. — J Med Chem

Cellosaurus cell lines

3 cell lines: 2 spontaneously immortalized cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_KY85	PathHunter CHO-K1 PROKR2 beta-arrestin	Spontaneously immortalized cell line	Female
CVCL_LB16	PathHunter U2OS PROKR2 Total GPCR Internalization	Cancer cell line	Female
CVCL_ZK63	GeneBLAzer PROKR2-Gqi5-NFAT-bla CHO-K1	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00140413	PHASE4	COMPLETED	Endocrine Dysfunction and Growth Hormone Deficiency in Children With Optic Nerve Hypoplasia
NCT00328926	PHASE4	TERMINATED	Luveris® (Lutropin Alfa for Injection) in Women With Hypogonadotropic Hypogonadism (Luteinizing Hormone [LH] Less Than [<] 1.2 International Unit Per Liter [IU/L])
NCT01403532	PHASE4	COMPLETED	Sequential Therapy for Hypogonadotropic Hypogonadism
NCT01454011	PHASE4	COMPLETED	The Effect of Testosterone Replacement on the High Density Lipoprotein Cholesterol Subgroups
NCT01601327	PHASE4	COMPLETED	Effects of Medications in Patients With Hypogonadism
NCT02310074	PHASE4	UNKNOWN	Efficacy and Safety of Pulsatile Gonadotropin Releasing Hormone Pump Treatment in Patients With Idiopathic Hypogonadotropic Hypogonadism
NCT02880280	PHASE4	UNKNOWN	Human Menopausal Gonadotropin Combining With Human Chorionic Gonadotropin Treat Congenital Hypogonadotropic Hypogonadism
NCT03490513	PHASE4	COMPLETED	Aromatase Inhibitors and Weight Loss in Severely Obese Men With Hypogonadism
NCT04456296	PHASE4	COMPLETED	A Study of the Effect of Testosterone Replacement Therapy on Blood Pressure in Adult Male Participants With Hypogonadism
NCT05205837	PHASE4	TERMINATED	A Randomized, Double-blinded, Clinical, Placebo-controlled Trial on the Effects of Therapy With Letrozole and hUman Choriongonadotropin in Male Hypogonadism Induced by Illicit Use of Anabolic Androgenic Steroids- The LUCAS Trial
NCT03687606	PHASE4	UNKNOWN	Efficacy and Safety of Long Term Use of hCG or hCG Plus hMG in Males With Isolated Hypogonadotropic Hypogonadism (IHH)
NCT01103518	PHASE4	UNKNOWN	Ethinyl Estradiol and Cyproterone Acetate in Irregular Menstruation
NCT01206153	PHASE4	COMPLETED	Metformin for Treatment Antipsychotic Induced Amenorrhea in Female Schizophrenic Patients
NCT02393482	PHASE4	UNKNOWN	Psychological Impact of Amenorrhea in Women With Endometriosis
NCT01388907	PHASE4	COMPLETED	Efficacity Assessment of PREVADH® in Adhesion Prevention in Gynaecologic Surgery
NCT01430650	PHASE4	COMPLETED	Endometrial Priming for Embryo Transfer
NCT02607319	PHASE4	COMPLETED	Low Molecular Weight Heparin to Improve Pregnancy Outcome in Patients With Recurrent Implantation Failure
NCT03169166	PHASE4	COMPLETED	The Use of GnRH Agonist Trigger for Final Follicle Maturation in Women Undergoing Assisted Reproductive Technologies
NCT03177122	PHASE4	UNKNOWN	Myo-Inositol- Based Co-treatment in Women With PCOS Undergoing Assisted Reproductive Technology
NCT03477929	PHASE4	UNKNOWN	Cetrorelix and Ganirelix Flexible Protocol for (IVF)
NCT03619707	PHASE4	COMPLETED	Oral Versus Vaginal Progesterone in the Luteal Support in Cryo-warmed Embryo Transfer Cycles
NCT03846544	PHASE4	COMPLETED	Double Pick up in Poor Prognosis Women
NCT05725512	PHASE4	RECRUITING	Prednisolone Administration in Patients With Unexplained REcurrent MIscarriages
NCT06195163	PHASE4	NOT_YET_RECRUITING	TRAP Study: Testosterone for Androgen Receptor Polymorphism
NCT06763926	PHASE4	NOT_YET_RECRUITING	Intranasal Nafarelin For Triggering Oocyte Maturation
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT06760546	PHASE3	RECRUITING	A Trial of Setmelanotide in Patients With Congenital Hypothalamic Obesity (Sub-study of NCT05774756)
NCT00467870	PHASE3	COMPLETED	Long-term Safety Study of Intramuscular Injections of 750 mg and 1000 mg Testosterone Undecanoate in Hypogonadal Men
NCT00962637	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Androxal™ Treatment in Men With Secondary Hypogonadism
NCT01067365	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Androxal Treatment in Men With Secondary Hypogonadism
NCT01532414	PHASE3	COMPLETED	Phase III Study to Evaluated Morning Testosterone Normalization in Men With Secondary Hypogonadism
NCT01534208	PHASE3	COMPLETED	Safety Study of Enclomiphene Citrate in the Treatment of Men With Secondary Hypogonadism
NCT01709331	PHASE3	COMPLETED	A Study of the Efficacy and Safety of Corifollitropin Alfa (MK-8962) in Combination With Human Chorionic Gonadotropin (hCG) in Adult Men With Hypogonadotropic Hypogonadism (HH) (P07937)
NCT01739582	PHASE3	COMPLETED	An Extension Study of Enclomiphene Citrate in the Treatment of Men With Secondary Hypogonadism
NCT01739595	PHASE3	COMPLETED	Phase III Study to Evaluate Morning Testosterone Normalization in Overweight Men With Secondary Hypogonadism
NCT01993212	PHASE3	COMPLETED	A Randomized, Double Blind, Placebo-Controlled, Multi-Center Phase III Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Testosterone and Sperm Concentration Following Treatment With 12.5 mg or 25 mg Androxal or AndroGel 1.62%
NCT01993225	PHASE3	COMPLETED	A Randomized, Double Blind, Placebo-Controlled, Multi-Center Phase III Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Testosterone and Sperm Concentration Following Treatment With 12.5 mg or 25 mg Androxal or AndroGel 1.62%
NCT02110368	PHASE3	COMPLETED	Bioequivalence Study of Test and Reference Testosterone Topical Gel, 1.62% Metered Pump in Testosterone Deficient Adult Male Subjects Under Fasting Conditions
NCT03019575	PHASE3	COMPLETED	Efficacy and Safety of Corifollitropin Alfa (MK-8962) in Combination With Human Chorionic Gonadotropin (hCG) in Adolescent Males With Hypogonadotropic Hypogonadism (HH) (MK-8962-043)