PROK2

Summary

PROK2 (prokineticin 2, HGNC:18455) is a protein-coding gene on chromosome 3p13, encoding Prokineticin-2 (Q9HC23). May function as an output molecule from the suprachiasmatic nucleus (SCN) that transmits behavioral circadian rhythm.

This gene encodes a protein expressed in the suprachiasmatic nucleus (SCN) circadian clock that may function as the output component of the circadian clock. The secreted form of the encoded protein may also serve as a chemoattractant for neuronal precursor cells in the olfactory bulb. Proteins from other vertebrates which are similar to this gene product were isolated based on homology to snake venom and secretions from frog skin, and have been shown to have diverse functions. Mutations in this gene are associated with Kallmann syndrome 4. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 60675 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypogonadotropic hypogonadism 4 with or without anosmia (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 93 total — 4 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 81
• MANE Select transcript: NM_001126128

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18455
Approved symbol	PROK2
Name	prokineticin 2
Location	3p13
Locus type	gene with protein product
Status	Approved
Aliases	PK2, BV8, MIT1, KAL4
Ensembl gene	ENSG00000163421
Ensembl biotype	protein_coding
OMIM	607002
Entrez	60675

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000295619, ENST00000353065

RefSeq mRNA: 2 — MANE Select: NM_001126128 NM_001126128, NM_021935

CCDS: CCDS2916, CCDS46868

Canonical transcript exons

ENST00000295619 — 4 exons

Exon	Start	End
ENSE00001074301	71774445	71774507
ENSE00001074305	71781467	71781592
ENSE00001829614	71784957	71785148
ENSE00001905962	71771655	71772828

Expression profiles

Bgee: expression breadth ubiquitous, 159 present calls, max score 97.68.

FANTOM5 (CAGE): breadth broad, TPM avg 3.8193 / max 1530.1604, expressed in 233 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
43111	1.9401	139
43110	0.4328	79
43112	0.3564	79
43114	0.3118	45
43109	0.2752	53
43115	0.2339	47
43116	0.1578	24
43113	0.1113	28

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
blood	UBERON:0000178	97.68	gold quality
bone marrow	UBERON:0002371	91.28	gold quality
trabecular bone tissue	UBERON:0002483	87.20	gold quality
leukocyte	CL:0000738	86.22	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.11	gold quality
monocyte	CL:0000576	85.85	gold quality
spleen	UBERON:0002106	83.68	gold quality
bone marrow cell	CL:0002092	83.03	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.76	gold quality
granulocyte	CL:0000094	82.25	gold quality
right lung	UBERON:0002167	79.22	gold quality
upper lobe of left lung	UBERON:0008952	76.90	gold quality
vermiform appendix	UBERON:0001154	76.86	gold quality
buccal mucosa cell	CL:0002336	76.75	silver quality
upper lobe of lung	UBERON:0008948	75.73	gold quality
left testis	UBERON:0004533	74.20	gold quality
right testis	UBERON:0004534	74.01	gold quality
testis	UBERON:0000473	73.42	gold quality
palpebral conjunctiva	UBERON:0001812	72.46	gold quality
caecum	UBERON:0001153	69.01	gold quality
lung	UBERON:0002048	68.30	gold quality
epithelial cell of pancreas	CL:0000083	67.15	silver quality
pancreatic ductal cell	CL:0002079	66.36	silver quality
adult organism	UBERON:0007023	64.05	gold quality
nasal cavity epithelium	UBERON:0005384	63.94	silver quality
decidua	UBERON:0002450	63.24	gold quality
omental fat pad	UBERON:0010414	62.66	gold quality
peritoneum	UBERON:0002358	62.60	gold quality
adipose tissue of abdominal region	UBERON:0007808	62.43	gold quality
gall bladder	UBERON:0002110	61.06	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.52
E-GEOD-106540	no	151.36

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ASCL1, DLX1, NEUROG1, STAT3

miRNA regulators (miRDB)

107 targeting PROK2, 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-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482

Literature-anchored findings (GeneRIF, showing 40)

• Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus. (PMID:12024206)
• Bv8 and EG-VEGF, along with other factors such as VEGF-A, may maintain the integrity and also regulate proliferation of the blood vessels in the testis (PMID:12604792)
• Paracrine role for the PKs and their receptors in endometrial vascular function. (PMID:15126578)
• potentially modulates growth, survival, and function of cells of the innate and adaptive immune systems, possibly through autocrine or paracrine signaling mechanisms (PMID:15548611)
• 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)
• Homozygous loss-of-function PROK2 mutations cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism (PMID:17959774)
• The identification of PROK2 biallelic mutations, that is, a missense mutation, p.R73C, and a frameshift mutation, c.163delA, in two out of 273 patients presenting as sporadic cases, is reported. (PMID:18285834)
• PK2/Bv8 expression decreases as the liver evolves towards cancer and does not correlate with HCC angiogenesis (PMID:18300343)
• 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)
• no mutations found in Kallmann syndrome (PMID:18723471)
• Bv8 expression is regulated by several cytokines in a cell type-specific fashion (PMID:19336519)
• 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)
• Review. Role of prokineticins in inflammatory and contractile pathways at parturition in humans. (PMID:20172976)
• 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 PROK2 in food intake and circadian rhythms (Review) (PMID:20389090)
• Data suggest that elevated prokineticin 2 levels, as a consequence of gastrointestinal tract inflammation, induce visceral pain via prokineticin receptors. (PMID:22050240)
• Induction of Bv8 expression by granulocyte colony-stimulating factor in CD11b+Gr1+ cells: key role of Stat3 signaling. (PMID:22528488)
• Three PROKR2 mutations previously described in Kallmann syndrome and one new PROK2 mutation were found in patients with isolated congenital anosmia. (PMID:23082007)
• We could not implicate the ligand PROK2 in congenital hypopituitarism and septo-optic dysplasia. (PMID:23386640)
• A novel role of BV8 in promoting oncogenesis intrinsic to malignant cells of myeloid origin. (PMID:23548897)
• No abnormalities were found in the patient group for the PROKR2 and GNRH1genes. In addition, no genomic rearrangements were identified in the healthy control individuals for the described genes (PMID:24002956)
• PROK2 signaling in humans is not required for central circadian pacemaker function. (PMID:24423319)
• study found a novel mutation in PROK2 in two male siblings presenting normosmic congenital hypogonadotropic hypogonadism, in whom a mutation in the GNRHR gene had been previously described, suggesting the possibility of a digenic inheritance (PMID:25531638)
• EG-VEGF, BV8, and PROKR2 gene expression is approximately five, four, and two times higher in cystic fibrosis lungs compared with controls. (PMID:26047640)
• PROK2 significantly increased in human fetal ovary across gestation. (PMID:26192875)
• Suggest PROK2 as an angiogenic growth factor in colorectal cancer. (PMID:26317645)
• 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)
• Prokineticin-2 is correlated with various cardiometabolic risk factors. (PMID:26728949)
• The results indicate that PK2 over-production perpetuates psoriatic symptoms by creating PK-2-IL-1 vicious loop. PK2 is a central player in psoriasis and a promising psoriasis-specific target. (PMID:27887936)
• infiltrating neutrophils and 4T1 cells abundantly expressed prokineticin-2 (Prok2) and its receptor, Prokr1, respectively. Finally, the administration of 5-FU after the resection of the primary tumor failed to augment lung metastasis in the mice receiving Prokr1-deleted 4T1 cells. (PMID:29643149)
• In PK2-mediated anti-adipogenic signaling, KDM6A stabilizes and increases cytoplasmic beta-catenin levels to repress peroxisome proliferator-activated receptor-gamma expression and activity. Findings offer additional molecular targets to manipulate hEPDCs-involved tissue repair/regeneration in cardiometabolic and ischemic heart diseases. (PMID:29873146)
• Results reveal that PK2 regulates a novel neuron-astrocyte signaling mechanism by promoting an alternative A2 protective phenotype in astrocytes. PK2-induced astrocyte reactivity leads to an increase in antioxidant and anti-inflammatory proteins while increasing glutamate uptake, along with decreased inflammatory factors. (PMID:30277602)
• We demonstrated a significant upregulation of PROK2 levels in brain tissues of Abeta1-42 i.c.v. injected rats, transgenic AD mice (Tg2576), and in the hippocampus of AD patients. Additionally, through a pilot study, an approximate twofold increase of PROK2 levels has been proved in the serum of AD patients, compared to the control subjects, identifying a potential blood-based biomarker of the disease. (PMID:31766244)
• Roles of Prokineticin 2 in Subarachnoid Hemorrhage-Induced Early Brain Injury via Regulation of Phenotype Polarization in Astrocytes. (PMID:32572760)
• Silencing PROK2 Inhibits Invasion of Human Cervical Cancer Cells by Targeting MMP15 Expression. (PMID:32887509)
• The novel function of miR-3195 for mutant PROK2 (c.223-4C>A) degradation. (PMID:33140874)
• Pleiotropic effects of prokineticin 2 in the control of energy metabolism. (PMID:33932486)
• Prokineticin-2 prevents neuronal cell deaths in a model of traumatic brain injury. (PMID:34244497)
• Differential inflammation-mediated function of prokineticin 2 in the synovial fibroblasts of patients with rheumatoid arthritis compared with osteoarthritis. (PMID:34526577)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	prok1	ENSDARG00000073948
danio_rerio	prok2	ENSDARG00000091616
mus_musculus	Prok2	ENSMUSG00000030069
rattus_norvegicus	Prok2	ENSRNOG00000010898

Paralogs (1): PROK1 (ENSG00000143125)

Protein

Protein identifiers

Prokineticin-2 — Q9HC23 (reviewed: Q9HC23)

Alternative names: Protein Bv8 homolog

All UniProt accessions (1): Q9HC23

UniProt curated annotations — full annotation on UniProt →

Function. May function as an output molecule from the suprachiasmatic nucleus (SCN) that transmits behavioral circadian rhythm. May also function locally within the SCN to synchronize output. Potently contracts gastrointestinal (GI) smooth muscle.

Subcellular location. Secreted.

Tissue specificity. Expressed in the testis and, at low levels, in the small intestine.

Disease relevance. Hypogonadotropic hypogonadism 4 with or without anosmia (HH4) [MIM:610628] 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 PROK2 as well as in other HH-associated genes including PROKR2.

Induction. Activated by CLOCK and BMAL1 heterodimers and light; inhibited by period genes (PER1, PER2 and PER3) and cryptochrome genes (CRY1 and CRY2).

Similarity. Belongs to the AVIT (prokineticin) family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9HC23-1	1	yes
Q9HC23-2	2

RefSeq proteins (2): NP_001119600, NP_068754 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009523	Prokineticin	Family
IPR023569	Prokineticin_domain	Domain

Pfam: PF06607

UniProt features (14 total): sequence variant 6, disulfide bond 5, signal peptide 1, chain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HC23-F1	69.22	0.05

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 (5): 34–46, 40–58, 45–107, 68–115, 109–125

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: 313 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, GOBP_CIRCADIAN_RHYTHM, BENPORATH_ES_WITH_H3K27ME3, GOBP_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_SMOOTH_MUSCLE_CONTRACTION, TATTATA_MIR374, AP4_Q6, RACCACAR_AML_Q6, GOBP_MALE_GAMETE_GENERATION, CHX10_01, AAAYRNCTG_UNKNOWN, CAGCTG_AP4_Q5, GOBP_TAXIS, GOBP_POSITIVE_REGULATION_OF_MUSCLE_CONTRACTION, GOBP_SENSORY_PERCEPTION_OF_PAIN

GO Biological Process (13): angiogenesis (GO:0001525), endothelial cell proliferation (GO:0001935), chemotaxis (GO:0006935), inflammatory response (GO:0006954), G protein-coupled receptor signaling pathway (GO:0007186), positive regulation of cytosolic calcium ion concentration (GO:0007204), neuropeptide signaling pathway (GO:0007218), spermatogenesis (GO:0007283), circadian rhythm (GO:0007623), sensory perception of pain (GO:0019233), negative regulation of apoptotic process (GO:0043066), positive regulation of smooth muscle contraction (GO:0045987), rhythmic process (GO:0048511)

GO Molecular Function (2): G protein-coupled receptor binding (GO:0001664), protein binding (GO:0005515)

GO Cellular Component (1): extracellular region (GO:0005576)

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
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
epithelial cell proliferation	1
response to chemical	1
taxis	1
defense response	1
G protein-coupled receptor activity	1
signal transduction	1
regulation of biological quality	1
G protein-coupled receptor signaling pathway	1
developmental process involved in reproduction	1
male gamete generation	1
rhythmic process	1
sensory perception	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
smooth muscle contraction	1
regulation of smooth muscle contraction	1
positive regulation of muscle contraction	1
biological_process	1
signaling receptor binding	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1198 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PROK2	PROKR2	Q8NFJ6	999
PROK2	PROKR1	Q8TCW9	994
PROK2	ANOS1	P23352	945
PROK2	GNRH1	P01148	897
PROK2	CHD7	Q9P2D1	870
PROK2	NSMF	Q6X4W1	868
PROK2	TACR3	P29371	856
PROK2	KISS1R	Q969F8	841
PROK2	TAC3	Q9UHF0	816
PROK2	GNRHR	P30968	789
PROK2	FGFR1	P11362	788
PROK2	KISS1	Q15726	776
PROK2	CLPS	P04118	733
PROK2	FGF8	P55075	727
PROK2	ADCY3	O60266	719

IntAct

6 interactions, top by confidence:

A	B	Type	Score
TMBIM1	PROK2	psi-mi:“MI:0915”(physical association)	0.560
PROK2	CPE	psi-mi:“MI:0914”(association)	0.350
PROK2	POTEF	psi-mi:“MI:0914”(association)	0.350
TMBIM1	PROK2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (13): PROK2 (Two-hybrid), POF1B (Affinity Capture-MS), APLP2 (Affinity Capture-MS), LENG8 (Affinity Capture-MS), HAPLN3 (Affinity Capture-MS), VWDE (Affinity Capture-MS), CPE (Affinity Capture-MS), LRP1B (Affinity Capture-MS), GPR98 (Affinity Capture-MS), GAPDHS (Affinity Capture-MS), POTEF (Affinity Capture-MS), TMOD1 (Affinity Capture-MS), PROK2 (Affinity Capture-MS)

ESM2 similar proteins: A0A8K1YTU0, A2RUU4, B3EWT5, B6DCW1, B6DCW2, B6DCW4, B6DCW5, B6DCW6, B6DCW7, B6DCW8, B6DCX0, B6DCZ2, B6DCZ8, B6DD06, B6DD07, B6DD08, B6DD09, B6DD10, B6DD11, B6DD12, C8CK75, D2DGD9, D3ZVN1, P0CI88, P0CY68, P0CY69, P0DQE7, P0DRJ1, P25687, P58294, Q14A28, Q2XXR7, Q2XXR8, Q30KJ4, Q5Y4V9, Q6IV20, Q6UDR6, Q75WG5, Q7Z096, Q7Z5A9

Diamond homologs: P25687, P58294, P84909, Q14A28, Q2XXR7, Q2XXR8, Q5W280, Q863H5, Q8JFE6, Q8JFQ0, Q8JFX8, Q8JFX9, Q8JFY0, Q8JFY1, Q8JFY2, Q8R413, Q8R414, Q9HC23, Q9PW66, Q9QXU7, D2Y2C0, D2Y2E0, D2Y2E1, D2Y2E2, D2Y2E3, D2Y2E4, D2Y2E5, D2Y2E6, Q56R10, D2Y2E7, O94907, P42890, O54908

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PROK2	up-regulates	PROKR2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	7
Uncertain significance	42
Likely benign	23
Benign	9

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
1074123	NM_001126128.2(PROK2):c.100_112del (p.Cys34fs)	Pathogenic
156561	NM_001126128.2(PROK2):c.101G>A (p.Cys34Tyr)	Pathogenic
3603	NM_001126128.2(PROK2):c.163del (p.Ser54_Ile55insTer)	Pathogenic
562782	GRCh37/hg19 3p13(chr3:70618611-72399570)x1	Pathogenic
2690979	NM_001126128.2(PROK2):c.313C>T (p.His105Tyr)	Likely pathogenic
2690980	NM_001126128.2(PROK2):c.122G>A (p.Gly41Asp)	Likely pathogenic
3041834	NM_001126128.2(PROK2):c.223-2A>G	Likely pathogenic
3893212	NM_001126128.2(PROK2):c.370_373del (p.Ile124fs)	Likely pathogenic
4538441	NM_001126128.2(PROK2):c.62del (p.Thr21fs)	Likely pathogenic
4538450	NM_001126128.2(PROK2):c.286-1G>A	Likely pathogenic
4759226	NM_001126128.2(PROK2):c.2T>C (p.Met1Thr)	Likely pathogenic

SpliceAI

639 predictions. Top by Δscore:

Variant	Effect	Δscore
3:71781462:CTAA:C	donor_gain	1.0000
3:71781465:A:AC	donor_gain	1.0000
3:71781466:C:CC	donor_gain	1.0000
3:71781466:CTTTA:C	donor_gain	1.0000
3:71784951:GCTTA:G	donor_loss	1.0000
3:71784952:CTTA:C	donor_loss	1.0000
3:71784953:TTAC:T	donor_loss	1.0000
3:71784954:TAC:T	donor_loss	1.0000
3:71784955:A:AC	donor_gain	1.0000
3:71784955:AC:A	donor_gain	1.0000
3:71784955:ACC:A	donor_gain	1.0000
3:71784956:C:CC	donor_gain	1.0000
3:71784956:C:CG	donor_loss	1.0000
3:71784956:CC:C	donor_gain	1.0000
3:71784956:CCC:C	donor_gain	1.0000
3:71784956:CCCCG:C	donor_gain	1.0000
3:71772826:AACCT:A	acceptor_loss	0.9900
3:71772827:ACC:A	acceptor_loss	0.9900
3:71772829:CTA:C	acceptor_loss	0.9900
3:71772830:T:A	acceptor_loss	0.9900
3:71774536:CAA:C	acceptor_gain	0.9900
3:71774537:A:T	acceptor_gain	0.9900
3:71781470:A:AC	donor_gain	0.9900
3:71781471:C:CC	donor_gain	0.9900
3:71781588:CAAGC:C	acceptor_gain	0.9900
3:71784950:CGCTT:C	donor_loss	0.9900
3:71784955:ACCC:A	donor_gain	0.9900
3:71784956:CCCC:C	donor_gain	0.9900
3:71774443:ACCT:A	donor_gain	0.9800
3:71774444:CCTC:C	donor_gain	0.9800

AlphaMissense

837 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:71781536:C:A	W51C	0.997
3:71781536:C:G	W51C	0.997
3:71781542:A:C	S49R	0.996
3:71781542:A:T	S49R	0.996
3:71781544:T:G	S49R	0.996
3:71781570:C:G	C40S	0.993
3:71781571:A:T	C40S	0.993
3:71781516:C:G	C58S	0.992
3:71781517:A:T	C58S	0.992
3:71781516:C:T	C58Y	0.991
3:71781486:C:G	C68S	0.990
3:71781487:A:T	C68S	0.990
3:71781505:C:A	G62C	0.989
3:71781515:G:C	C58W	0.989
3:71781517:A:G	C58R	0.987
3:71781555:C:G	C45S	0.987
3:71781556:A:T	C45S	0.987
3:71781486:C:T	C68Y	0.986
3:71781521:C:A	R56S	0.986
3:71781521:C:G	R56S	0.986
3:71781552:C:G	C46S	0.986
3:71781553:A:T	C46S	0.986
3:71781588:C:T	C34Y	0.986
3:71781588:C:G	C34S	0.985
3:71781589:A:T	C34S	0.985
3:71781549:G:T	A47D	0.984
3:71781552:C:T	C46Y	0.984
3:71781485:G:C	C68W	0.983
3:71781487:A:G	C68R	0.982
3:71781551:A:C	C46W	0.982

dbSNP variants (sampled 300 via entrez): RS1000042800 (3:71781147 A>G), RS1000092857 (3:71779475 G>A), RS1000331930 (3:71781485 G>A), RS1000388520 (3:71780784 G>A,C), RS1000738854 (3:71780552 C>T), RS1000831501 (3:71785186 C>T), RS1000883784 (3:71785306 G>C), RS1001532402 (3:71776635 C>T), RS1001589572 (3:71773763 C>A,G,T), RS1001621392 (3:71785770 A>G), RS1001865822 (3:71777962 G>A), RS1001930999 (3:71780080 A>C,T), RS1001982002 (3:71777711 A>C), RS1002277570 (3:71784667 G>A), RS1002336790 (3:71784631 A>G)

Disease associations

OMIM: gene MIM:607002 | disease phenotypes: MIM:610628, MIM:147950

GenCC curated gene-disease

Disease	Classification	Inheritance
hypogonadotropic hypogonadism 4 with or without anosmia	Definitive	Semidominant
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 4 with or without anosmia	Definitive	SD

Mondo (5): disorder of sexual differentiation (MONDO:0002145), amenorrhea (MONDO:0001836), hypogonadotropic hypogonadism 4 with or without anosmia (MONDO:0012528), hypogonadotropic hypogonadism (MONDO:0018555), Kallmann syndrome (MONDO:0018800)

Orphanet (5): Difference of sex development (Orphanet:90771), Kallmann syndrome (Orphanet:478), Male infertility with spermatogenesis disorder (Orphanet:399775), Normosmic congenital hypogonadotropic hypogonadism (Orphanet:432), Male infertility with azoospermia or oligozoospermia due to single gene mutation (Orphanet:399805)

HPO phenotypes

81 total (30 of 81 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:0000134	Female hypogonadism
HP:0000144	Decreased fertility
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000316	Hypertelorism
HP:0000407	Sensorineural hearing impairment
HP:0000458	Anosmia
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000551	Color vision defect
HP:0000639	Nystagmus
HP:0000716	Depression
HP:0000739	Anxiety
HP:0000771	Gynecomastia
HP:0000786	Primary amenorrhea
HP:0000789	Infertility
HP:0000802	Impotence
HP:0000819	Diabetes mellitus

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST004625_72	Monocyte count	4.000000e-09
GCST006585_379	Blood protein levels	3.000000e-289
GCST009240_371	Serum metabolite levels (CMS)	3.000000e-10
GCST90002394_247	Monocyte percentage of white cells	6.000000e-12

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005091	monocyte count
EFO:0007989	monocyte percentage of leukocytes

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D000568	Amenorrhea	C23.550.568.500
D012734	Disorders of Sex Development	C12.050.351.875.253; C12.200.706.316; C12.800.316; C16.131.939.316; C19.391.119
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
C565696	Kallmann Syndrome 4 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

Binding affinities (BindingDB)

1 measured of 1 human assays (1 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
A457	IC50	102 nM

PubChem BioAssay actives

1 with measured affinity, of 1 total; 1 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	0.0400	uM

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, decreases methylation, increases expression	7
trichostatin A	decreases expression, increases expression, affects cotreatment	3
mercuric bromide	affects cotreatment, decreases expression	2
Vorinostat	affects cotreatment, decreases expression	2
Panobinostat	affects cotreatment, decreases expression	2
Diethylhexyl Phthalate	decreases expression, increases abundance, increases methylation	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects expression	1
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Ethanol	increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	1
Cisplatin	decreases expression	1
Copper	affects binding, decreases expression	1
Disulfiram	affects binding, decreases expression	1
Ivermectin	decreases expression	1
Ozone	increases expression	1
Tretinoin	increases expression	1
Aflatoxin B1	decreases methylation	1
Asbestos, Crocidolite	affects expression	1
Antirheumatic Agents	decreases expression	1
Cadmium Chloride	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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
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)
NCT06561594	PHASE3	NOT_YET_RECRUITING	To Evaluate Recombinant Human Follicle Stimulating Hormone-CTP Fusion Protein Injection or Placebo Combined With Chorionic Gonadotropin for Injection
NCT00827151	PHASE3	WITHDRAWN	Bone Mass Accrual in Adolescent Athletes
NCT00193661	PHASE2	COMPLETED	Observation Study of T-Gel (1%) in Treatment of Adolescent Boys With Hypogonadism
NCT00383656	PHASE2	UNKNOWN	Pulsatile GnRH in Anovulatory Infertility
NCT00697814	PHASE2	COMPLETED	Clomiphene in Males With Prolactinomas and Persistent Hypogonadism
NCT00706719	PHASE2	COMPLETED	To Evaluate Sperm Parameters in Men With Secondary Hypogonadism Previously Treated With Topical Testosterone
NCT00911586	PHASE2	COMPLETED	Pharmacokinetic Study to Determine Time to Steady-state
NCT01155518	PHASE2	TERMINATED	Hypogonadism in Young Men With Type 2 Diabetes
NCT01191320	PHASE2	COMPLETED	Study to Evaluate the Efficacy of Androxal in Controlling Blood Glucose in Men With Type-2 Diabetes Mellitus
NCT01270841	PHASE2	COMPLETED	Normalization of Morning Testosterone Levels in Men With Secondary Hypogonadism
NCT01386606	PHASE2	COMPLETED	The Effect on Androxal Versus Androgel on Morning Testosterone in Men With Secondary Hypogonadism (Low Testosterone)
NCT01894308	PHASE2	NOT_YET_RECRUITING	A Dose Ranging Study to Examine TDS-Testosterone 5%
NCT02369796	PHASE2	TERMINATED	A Phase 2a Pharmacodynamic Study of TAK-448 in Participants With Hypogonadotropic Hypogonadism
NCT02443090	PHASE2	UNKNOWN	Safety and Efficacy Study of Oral Fispemifene for the Treatment of Sexual Dysfunction in Hypogonadal Men
NCT02651688	PHASE2	COMPLETED	A Multi-Center Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Body Composition and Metabolic Parameters With Diet and Exercise in Conjunction With Treatment With 12.5 mg or 25 mg Enclomiphene