RXFP2

Summary

RXFP2 (relaxin family peptide receptor 2, HGNC:17318) is a protein-coding gene on chromosome 13q13.1, encoding Relaxin receptor 2 (Q8WXD0). Receptor for relaxin.

This gene encodes a member of the GPCR (G protein-coupled, 7-transmembrane receptor) family. Mutations in this gene are associated with cryptorchidism. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 122042 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cryptorchidism (Limited, GenCC) — +1 more curated relationship
• GWAS associations: 9
• Clinical variants (ClinVar): 136 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 1
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_130806

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17318
Approved symbol	RXFP2
Name	relaxin family peptide receptor 2
Location	13q13.1
Locus type	gene with protein product
Status	Approved
Aliases	GREAT, GPR106, INSL3R, RXFPR2
Ensembl gene	ENSG00000133105
Ensembl biotype	protein_coding
OMIM	606655
Entrez	122042

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000298386, ENST00000380314

RefSeq mRNA: 2 — MANE Select: NM_130806 NM_001166058, NM_130806

CCDS: CCDS53862, CCDS9342

Canonical transcript exons

ENST00000298386 — 18 exons

Exon	Start	End
ENSE00000907232	31791806	31792035
ENSE00000907234	31792678	31793088
ENSE00000938825	31797201	31797419
ENSE00001094289	31777376	31777447
ENSE00001094290	31786566	31786637
ENSE00001094291	31786383	31786454
ENSE00001094292	31765037	31765142
ENSE00001094294	31761724	31761801
ENSE00001094296	31778512	31778583
ENSE00001094298	31775318	31775389
ENSE00001094301	31781671	31781742
ENSE00001094304	31774620	31774691
ENSE00001094306	31789122	31789193
ENSE00001094313	31782676	31782747
ENSE00001175525	31765956	31766027
ENSE00001175543	31758258	31758404
ENSE00003728452	31802146	31803389
ENSE00003847852	31739526	31739706

Expression profiles

Bgee: expression breadth broad, 61 present calls, max score 76.88.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1499 / max 43.7269, expressed in 27 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
134661	0.0612	15
134660	0.0585	18
134659	0.0302	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.88	silver quality
buccal mucosa cell	CL:0002336	72.84	silver quality
monocyte	CL:0000576	71.74	gold quality
leukocyte	CL:0000738	71.02	gold quality
bone marrow cell	CL:0002092	55.04	gold quality
granulocyte	CL:0000094	53.18	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	51.28	silver quality
left uterine tube	UBERON:0001303	47.03	gold quality
blood	UBERON:0000178	46.76	gold quality
smooth muscle tissue	UBERON:0001135	46.70	gold quality
right adrenal gland cortex	UBERON:0035827	46.65	gold quality
left adrenal gland	UBERON:0001234	45.33	gold quality
adrenal gland	UBERON:0002369	45.00	gold quality
adrenal cortex	UBERON:0001235	44.42	gold quality
cauda epididymis	UBERON:0004360	44.28	gold quality
left adrenal gland cortex	UBERON:0035825	44.26	gold quality
right adrenal gland	UBERON:0001233	44.07	gold quality
nucleus accumbens	UBERON:0001882	43.93	gold quality
putamen	UBERON:0001874	43.61	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
secondary oocyte	CL:0000655	42.57	gold quality
vastus lateralis	UBERON:0001379	41.41	gold quality
quadriceps femoris	UBERON:0001377	41.37	gold quality
superficial temporal artery	UBERON:0001614	41.33	gold quality
oviduct epithelium	UBERON:0004804	41.27	gold quality
palpebral conjunctiva	UBERON:0001812	41.10	gold quality
mucosa of paranasal sinus	UBERON:0005030	40.98	gold quality
prefrontal cortex	UBERON:0000451	40.89	gold quality
upper leg skin	UBERON:0004262	40.81	silver quality
amniotic fluid	UBERON:0000173	40.69	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	5.21

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, DLX4, NFKBIA, SOX9, TCF21, TCF3

miRNA regulators (miRDB)

21 targeting RXFP2, 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-4482-3P	99.98	72.50	3147
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-12130	99.75	65.47	452
HSA-MIR-4652-3P	99.33	70.02	2742
HSA-MIR-6809-5P	99.13	68.45	1223
HSA-MIR-6830-5P	99.01	68.73	1884
HSA-MIR-138-2-3P	98.91	68.33	1643
HSA-MIR-181A-2-3P	98.91	67.60	1168
HSA-MIR-6769B-5P	98.73	64.91	1092
HSA-MIR-6509-3P	98.32	67.33	1343
HSA-MIR-92A-1-5P	98.28	64.51	631
HSA-MIR-6769A-5P	97.99	64.16	851
HSA-MIR-5189-3P	97.52	66.33	487
HSA-MIR-8069	97.05	66.79	718
HSA-MIR-4701-5P	96.45	68.41	1121
HSA-MIR-588	96.45	68.36	1127
HSA-MIR-6742-5P	96.32	64.01	869
HSA-MIR-6796-5P	95.37	66.08	1120

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 36)

• the only clinical consequence of alterations of the INSL3-LGR8 system seems to be failure of the testis to normally descend in the scrotum during embryonic development, without affecting the spermatogenic and endocrine components of the testis itself (PMID:12970298)
• mutations involving the human LGR8 gene do not represent a frequent cause of cryptorchidism in the Finnish population (PMID:14656401)
• recurrent T222P mutation in the LGR8 gene was not found in any of the patients. These data show for the first time a lack of association between genetic factors necessary for correct testicular descent and anorchia. (PMID:15579790)
• LGR8 signal is activated by the relaxin-like factor (PMID:15708846)
• LGR8.1 spliced isoform is expressed at the cell surface, unable to stimulate cAMP production. (PMID:16051677)
• Alanine-substituted analogs were used to identify the key residues of INSL3 that are responsible for the interaction with the ectodomain of LGR8. These include Arg(B16) and Val(B19), with His(B12) and Arg(B20) playing a secondary role. (PMID:16867980)
• Novel allele of LGR8 (R223K) found in one patient with retractile testes. (PMID:16926383)
• The essential role of the LDLa module in LGR7 and LGR8 function is reported. (PMID:16963451)
• The V18M mutation in the insulin-like factor 3 signal peptide had a significant deleterious effect in activating LGR8 receptor in ex vivo studies (PMID:17437853)
• predicted the complete INSL3/LGR8 primary binding site, including interactions between INSL3 His-B12 and LGR8 Trp-177, INSL3 Val-B19 and LGR8 Ile-179, and INSL3 Arg-B20 with LGR8 Asp-181 and Glu-229 (PMID:17473281)
• negative cooperativity is present and that INSL3-RXFP2 binding shows both similarities and differences with insulin binding to the insulin receptor (PMID:18063691)
• T222P mutation cannot be considered either causative or a susceptibility factor for cryptorchidism. (PMID:18073304)
• analysis of truncated human relaxin-2 and -3 (H2 and H3) relaxin peptides and their binding and cAMP activities on RXFP1, RXFP2, and RXFP3 (PMID:18434306)
• No association between T222P/LGR8 mutation and cryptorchidism in the Moroccan population (PMID:18772597)
• The apparent lack of classical regulation for RXFP1 and RXFP2 provides the molecular basis for the prolonged signaling and physiological actions of relaxin and related peptides (PMID:19279230)
• Ligand-mediated activation of RXFP1 and RXFP2 is a complex process involving various domains of the receptors (PMID:19416161)
• relaxin binds with high affinity to the leucine-rich repeats of RXFP2 in a manner similar to INSL3 binding to its receptor (PMID:19416162)
• Several missense mutations were described in both the INSL3 and RXFP2 genes and a novel V39G INSL3 mutation in a patient with cryptorchidism was identified (PMID:19416188)
• This study confirmed the association between INSL3 and RXFP2 gene mutations and human cryptorchidism. (PMID:19416190)
• Data link RXFP2 gene mutations with human osteoporosis. (PMID:19416191)
• Data show that synthetic parallel dimer of the B-chain of INSL3 is a potent inhibitor of the native peptide’s binding to its receptor, RXFP2. (PMID:20560146)
• haplotype analysis of the RXFP2 gene in T222P carriers and their parents showed that this variant is linked to the previously inferred C-C-G-A-13 haplotype and consequently provides further support to the ‘founder effect’ hypothesis (PMID:20636340)
• higher expression of LGR8 may facilitate tumor invasiveness in the early clinical stage of hepatocellular carcinoma. (PMID:21789898)
• relaxin-2 and its receptors RXFP1 and RXFP2 are expressed in GSV and their expression is significantly decreased in varicose GSV (PMID:22737225)
• These results provide new mechanistic insights into the binding and activation events of RXFP1 and RXFP2 by their native hormone ligands. (PMID:22973049)
• Identification of key residues essential for the structural fold and receptor selectivity within the A-chain of human gene-2 (H2) relaxin (PMID:23024363)
• Findings suggest a novel and gender-specific role for INSL3 and cognate receptor RXFP2 signaling in ocular surface homeostasis. (PMID:23539510)
• Mapping key regions of the RXFP2 low-density lipoprotein class-A module that are involved in signal activation. (PMID:24983702)
• In the TMD discovery cohort, sex-stratified analysis identified 2 additional genome-wide significant loci in females. One lying upstream of the relaxin/insulin-like family peptide receptor 2 ( RXP2) (chromosome 13, rs60249166,[OR] = 0.65, P = 3.6 x 10(-8)) was replicated among females in the meta-analysis (1-tailed P = 0.052). The other (chromosome 17, rs1531554, OR = 0.68, P = 2.9 x 10(-8)) was replicated among f (PMID:28081371)
• Recessive variants in the RXFP2 gene underlie familial cryptorchidism. (PMID:31167797)
• Human amniotic fluid-based exposure levels of phthalates and bisphenol A mixture reduce INSL3/RXFP2 signaling. (PMID:32126385)
• Expression of RXFP2 receptor on human spermatozoa and the anti-apoptotic and antioxidant effects of insulin-like factor 3. (PMID:32557760)
• Structural Insights into the Unique Modes of Relaxin-Binding and Tethered-Agonist Mediated Activation of RXFP1 and RXFP2. (PMID:34454945)
• Bi-allelic variants in INSL3 and RXFP2 cause bilateral cryptorchidism and male infertility. (PMID:37208861)
• Discovery of RXFP2 genetic association in resistant hypertensive men and RXFP2 antagonists for the treatment of resistant hypertension. (PMID:38851835)
• Biallelic RXFP2 variants lead to congenital bilateral cryptorchidism and male infertility, supporting a role of RXFP2 in spermatogenesis. (PMID:39222519)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	rxfp2b	ENSDARG00000019660
danio_rerio	rxfp2a	ENSDARG00000032820
mus_musculus	Rxfp2	ENSMUSG00000053368
rattus_norvegicus	Rxfp2	ENSRNOG00000000897

Paralogs (22): IGFALS (ENSG00000099769), TLR8 (ENSG00000101916), LRRC17 (ENSG00000128606), CD180 (ENSG00000134061), TLR4 (ENSG00000136869), TLR2 (ENSG00000137462), LRRC32 (ENSG00000137507), LRRC3 (ENSG00000160233), LRRC53 (ENSG00000162621), TLR3 (ENSG00000164342), VASN (ENSG00000168140), RXFP1 (ENSG00000171509), NRROS (ENSG00000174004), TLR10 (ENSG00000174123), TLR1 (ENSG00000174125), TLR6 (ENSG00000174130), LRRC3B (ENSG00000179796), TSKU (ENSG00000182704), TLR5 (ENSG00000187554), TLR7 (ENSG00000196664), LRIT2 (ENSG00000204033), LRRC3C (ENSG00000204913)

Protein

Protein identifiers

Relaxin receptor 2 — Q8WXD0 (reviewed: Q8WXD0)

Alternative names: G-protein coupled receptor 106, G-protein coupled receptor affecting testicular descent, Leucine-rich repeat-containing G-protein coupled receptor 8, Relaxin family peptide receptor 2

All UniProt accessions (1): Q8WXD0

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for relaxin. The activity of this receptor is mediated by G proteins leading to stimulation of adenylate cyclase and an increase of cAMP. May also be a receptor for Leydig insulin-like peptide (INSL3).

Subcellular location. Cell membrane.

Tissue specificity. Expressed mainly in the brain, kidney, muscle, testis, thyroid, uterus, peripheral blood cells and bone marrow.

Disease relevance. Cryptorchidism (CRYPTO) [MIM:219050] One of the most frequent congenital abnormalities in humans, involving 2-5% of male births. Cryptorchidism is associated with increased risk of infertility and testicular cancer. The disease is caused by variants affecting the gene represented in this entry.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q8WXD0-1	1	yes
Q8WXD0-2	2

RefSeq proteins (2): NP_001159530, NP_570718* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR001611	Leu-rich_rpt	Repeat
IPR002172	LDrepeatLR_classA_rpt	Repeat
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR008112	Relaxin_rcpt	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain
IPR023415	LDLR_class-A_CS	Conserved_site
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR036055	LDL_receptor-like_sf	Homologous_superfamily

Pfam: PF00001, PF00057, PF13855

UniProt features (42 total): repeat 10, topological domain 8, transmembrane region 7, glycosylation site 5, disulfide bond 4, sequence variant 2, chain 1, domain 1, splice variant 1, mutagenesis site 1, helix 1, strand 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2M96	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WXD0-F1	81.25	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 (4): 45–58, 52–71, 65–80, 495–573

Glycosylation sites (5): 54, 138, 274, 335, 378

Mutagenesis-validated functional residues (1):

Position	Phenotype
647	leads to constitutive increase of basal camp.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-418555	G alpha (s) signalling events
R-HSA-444821	Relaxin receptors
R-HSA-162582	Signal Transduction
R-HSA-372790	Signaling by GPCR
R-HSA-373076	Class A/1 (Rhodopsin-like receptors)
R-HSA-375276	Peptide ligand-binding receptors
R-HSA-388396	GPCR downstream signalling
R-HSA-500792	GPCR ligand binding

MSigDB gene sets: 0 (showing top):

GO Biological Process (9): oocyte maturation (GO:0001556), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway (GO:0007193), negative regulation of cell population proliferation (GO:0008285), male gonad development (GO:0008584), hormone-mediated signaling pathway (GO:0009755), negative regulation of apoptotic process (GO:0043066), signal transduction (GO:0007165), G protein-coupled receptor signaling pathway (GO:0007186)

GO Molecular Function (5): G protein-coupled peptide receptor activity (GO:0008528), protein-hormone receptor activity (GO:0016500), peptide hormone binding (GO:0017046), G protein-coupled receptor activity (GO:0004930), protein binding (GO:0005515)

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

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Signaling by GPCR	2
GPCR downstream signalling	1
Peptide ligand-binding receptors	1
Signal Transduction	1
GPCR ligand binding	1
Class A/1 (Rhodopsin-like receptors)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	2
signal transduction	2
G protein-coupled receptor activity	2
developmental process involved in reproduction	1
cell maturation	1
oocyte development	1
adenylate cyclase activator activity	1
adenylate cyclase inhibitor activity	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
gonad development	1
development of primary male sexual characteristics	1
cellular response to hormone stimulus	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
peptide receptor activity	1
signaling receptor activity	1
hormone binding	1
transmembrane signaling receptor activity	1
G protein-coupled receptor signaling pathway	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1530 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RXFP2	INSL3	P51460	999
RXFP2	RLN2	P04090	978
RXFP2	RLN1	P04808	945
RXFP2	RLN3	Q8WXF3	867
RXFP2	INS	P01308	861
RXFP2	B3GLCT	Q6Y288	846
RXFP2	RXFP3	Q9NSD7	835
RXFP2	RXFP4	Q8TDU9	817
RXFP2	INSL5	Q9Y5Q6	753
RXFP2	NR5A1	Q13285	593
RXFP2	INSL6	Q9Y581	582
RXFP2	INSL4	Q14641	573
RXFP2	CFP	P27918	552
RXFP2	NPBWR2	P48146	524
RXFP2	ESR1	P03372	492

IntAct

4 interactions, top by confidence:

A	B	Type	Score
P		psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
RXFP2	LIMK1	psi-mi:“MI:0914”(association)	0.350

BioGRID (4): RXFP2 (Affinity Capture-Western), OSBPL8 (Affinity Capture-MS), CNPY4 (Affinity Capture-MS), LIMK1 (Affinity Capture-MS)

ESM2 similar proteins: A1A4H9, A2ARI4, A6NDA9, B0BLW3, B1H134, B1H234, D3ZTV3, D4A6D8, D4AC13, E5DHB5, E7FE13, F1MLX5, F1MT22, F1NUK7, F7D3V9, O43155, O60602, O75473, P0DM44, Q504C1, Q5R6B1, Q5R6T0, Q5R7M3, Q5RAC4, Q5XM32, Q66HV9, Q6PFC5, Q6QMG1, Q70AK3, Q7TNJ4, Q80ZD7, Q80ZD8, Q80ZD9, Q810C0, Q810C1, Q86SJ2, Q86UE6, Q8BGT1, Q8BLU0, Q8CBC6

Diamond homologs: O02721, P14763, P16235, P16473, P16582, P20395, P21463, P22888, P23945, P24014, P30730, P32212, P35376, P35378, P35379, P35409, P46023, P47750, P47799, P49059, P56495, P79763, Q27987, Q28005, Q28585, Q5GJ04, Q5R5V8, Q5XM32, Q6QMG1, Q6R6I6, Q6R6I7, Q6R6L8, Q6YNB6, Q7ZTV5, Q8R428, Q8SPP9, Q8WXD0, Q90674, Q91ZZ5, Q95179

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
RLN2	up-regulates	RXFP2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	86
Likely benign	10
Benign	35

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
2429749	NM_130806.5(RXFP2):c.1406del (p.Phe469fs)	Pathogenic
2429750	NM_130806.5(RXFP2):c.1015A>G (p.Asn339Asp)	Likely pathogenic

SpliceAI

2603 predictions. Top by Δscore:

Variant	Effect	Δscore
13:31758256:A:AG	acceptor_gain	1.0000
13:31758257:G:GG	acceptor_gain	1.0000
13:31758401:TGTGG:T	donor_loss	1.0000
13:31758402:GTG:G	donor_gain	1.0000
13:31758403:TGG:T	donor_loss	1.0000
13:31758405:G:GC	donor_loss	1.0000
13:31758406:TGAG:T	donor_loss	1.0000
13:31758407:GAGTG:G	donor_loss	1.0000
13:31761797:GTGCT:G	donor_gain	1.0000
13:31761802:G:GG	donor_gain	1.0000
13:31765143:G:GG	donor_gain	1.0000
13:31766025:GAT:G	donor_gain	1.0000
13:31786451:AGCT:A	donor_gain	1.0000
13:31786452:GCT:G	donor_gain	1.0000
13:31786452:GCTG:G	donor_gain	1.0000
13:31786455:G:GG	donor_gain	1.0000
13:31786549:A:AG	acceptor_gain	1.0000
13:31786549:AAT:A	acceptor_gain	1.0000
13:31786551:T:A	acceptor_gain	1.0000
13:31758253:T:G	acceptor_gain	0.9900
13:31758253:TGTA:T	acceptor_loss	0.9900
13:31758254:GTA:G	acceptor_loss	0.9900
13:31758255:TA:T	acceptor_loss	0.9900
13:31758256:AGAT:A	acceptor_loss	0.9900
13:31758257:G:GT	acceptor_loss	0.9900
13:31758257:GAT:G	acceptor_gain	0.9900
13:31758400:CTGTG:C	donor_gain	0.9900
13:31758405:G:GG	donor_gain	0.9900
13:31765138:TTACT:T	donor_gain	0.9900
13:31766024:AGAT:A	donor_gain	0.9900

AlphaMissense

5023 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:31758374:T:A	C71S	0.995
13:31758375:G:C	C71S	0.995
13:31758356:T:A	C65S	0.994
13:31758357:G:C	C65S	0.994
13:31802190:A:C	S684R	0.994
13:31802192:T:A	S684R	0.994
13:31802192:T:G	S684R	0.994
13:31792683:G:C	D461H	0.993
13:31792684:A:T	D461V	0.993
13:31792685:T:A	D461E	0.993
13:31792685:T:G	D461E	0.993
13:31786454:T:C	L334P	0.992
13:31792684:A:C	D461A	0.992
13:31792938:T:A	W546R	0.992
13:31792938:T:C	W546R	0.992
13:31775389:T:C	L214P	0.991
13:31791959:T:A	N433K	0.991
13:31791959:T:G	N433K	0.991
13:31792695:G:C	G465R	0.991
13:31786637:T:C	L358P	0.990
13:31792684:A:G	D461G	0.990
13:31782747:T:C	L310P	0.989
13:31792785:T:A	C495S	0.989
13:31792786:G:C	C495S	0.989
13:31802194:C:A	A685D	0.989
13:31758317:T:A	C52S	0.988
13:31758318:G:C	C52S	0.988
13:31791927:T:A	W423R	0.988
13:31791927:T:C	W423R	0.988
13:31792032:T:C	C458R	0.988

dbSNP variants (sampled 300 via entrez): RS1000013759 (13:31794333 G>A), RS1000057787 (13:31756525 C>A), RS1000070994 (13:31756276 A>T), RS1000128909 (13:31767505 A>C,G), RS1000154621 (13:31797935 C>G), RS1000160786 (13:31767950 C>T), RS1000174008 (13:31770744 A>G,T), RS1000275915 (13:31764211 C>T), RS1000319940 (13:31761416 A>G), RS1000367985 (13:31753202 T>C), RS1000375664 (13:31773479 A>G), RS1000450342 (13:31758712 T>C), RS1000505713 (13:31798255 C>T), RS1000527221 (13:31783004 G>A,T), RS1000534733 (13:31787665 A>C)

Disease associations

OMIM: gene MIM:606655 | disease phenotypes: MIM:219050

GenCC curated gene-disease

Disease	Classification	Inheritance
cryptorchidism	Limited	Autosomal recessive
disorder of sexual differentiation	Limited	Autosomal recessive

Mondo (2): disorder of sexual differentiation (MONDO:0002145), cryptorchidism (MONDO:0009047)

Orphanet (1): Difference of sex development (Orphanet:90771)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000028	Cryptorchidism

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST006624_97	Systolic blood pressure	6.000000e-29
GCST007267_18	Systolic blood pressure	2.000000e-34
GCST007269_55	Pulse pressure	6.000000e-15
GCST007605_1	Glycated hemoglobin levels in type 1 diabetes	4.000000e-08
GCST007928_41	Medication use (diuretics)	2.000000e-11
GCST007929_65	Medication use (calcium channel blockers)	1.000000e-21
GCST007930_5	Medication use (agents acting on the renin-angiotensin system)	1.000000e-10
GCST008181_8	Spontaneous preterm birth without premature rupture of membranes	1.000000e-06
GCST010774_32	Essential hypertension (time to event)	2.000000e-08

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0005763	pulse pressure measurement
EFO:0004541	HbA1c measurement
EFO:0009928	Diuretic use measurement
EFO:0009930	Calcium channel blocker use measurement
EFO:0009931	Agents acting on the renin-angiotensin system use measurement
EFO:0006917	spontaneous preterm birth
EFO:0004918	age at diagnosis

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D003456	Cryptorchidism	C12.100.500.829.258; C12.200.294.829.258; C12.200.706.258; C12.800.258; C16.131.939.258; C19.391.829.258
D012734	Disorders of Sex Development	C12.050.351.875.253; C12.200.706.316; C12.800.316; C16.131.939.316; C19.391.119

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1628482 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: gpcr — Relaxin family peptide receptors

Most potent curated ligand interactions (20 total), top 20:

Ligand	Action	Affinity	Parameter
INSL3	Full agonist	10.35	pKd
INSL3 [A(5-26):B(7-27)]	Agonist	10.0	pEC50
[125I]INSL3 (human)	Full agonist	10.0	pKd
[33P]relaxin (human)	Full agonist	9.2	pKd
A(9-26)INSL3	Antagonist	9.14	pKi
relaxin	Full agonist	9.13	pEC50
europium-labelled INSL3	Full agonist	9.0	pKd
relaxin-1	Full agonist	8.8	pKi
NanoLuc-INSL3	Agonist	8.7	pKd
A(10-24)INSL3	Antagonist	8.67	pKi
A(C10/15S)INSL3	Antagonist	8.59	pKi
INSL3 B chain dimer analogue 8	Antagonist	8.5	pKi
A(Δ10/15C)INSL3	Antagonist	8.32	pKi
relaxin	Full agonist	7.9	pKi
relaxin	Full agonist	7.8	pKi
relaxin-3	Full agonist	7.0	pKi
cyclic INSL3 B-chain analogue 6	Antagonist	6.65	pKi
compound 6641	Agonist	6.42	pEC50
A(4-24)(B7-24)H2	Antagonist	6.0	pEC50
INSL3 B-chain analogue	Antagonist	5.1	pKi

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.48	AC50	3340	nM	CHEMBL3718470
5.13	AC50	7470	nM	CHEMBL3715750
5.03	AC50	9400	nM	CHEMBL3716158

CTD chemical–gene interactions

9 total (human), top 9 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases activity, increases methylation	2
Smoke	decreases expression, decreases reaction	2
butylbenzyl phthalate	increases expression	1
CGP 52608	affects binding, increases reaction	1
Decitabine	decreases expression, decreases reaction	1
Benzo(a)pyrene	increases methylation	1
Dibutyl Phthalate	increases activity	1
Diethylhexyl Phthalate	increases activity	1
Tretinoin	increases expression	1

ChEMBL screening assays

5 unique, capped per target: 3 functional, 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1738172	Functional	PUBCHEM_BIOASSAY: qHTS Assay for Agonists of the Relaxin Receptor RXFP1: RXFP2 Hit Validation. (Class of assay: confirmatory) [Related pubchem assays (depositor defined):AID2676, AID2703, AID489012]	PubChem BioAssay data set
CHEMBL4883589	Binding	PRESTO-Tango GPCRome screening (RXFP2)	Data for DCP probe UCSF924

Cellosaurus cell lines

1 cell lines: 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_KV77	cAMP Hunter CHO-K1 RXFP2 Gs	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02110745	PHASE4	COMPLETED	The Effect of Induction Technique on Postoperative Pain and Agitation
NCT04826484	PHASE3	TERMINATED	Opioid Reduction Initiative During Outpatient Pediatric Urologic Procedures Using Exparel
NCT01701778	PHASE2	COMPLETED	Caudal Versus Intravenous Dexmedetomidine for Supplementation of Caudal Analgesia in Children
NCT03718234	PHASE1	COMPLETED	Subcutaneous Hydrocortisone Children With Congenital Adrenal Hyperplasia
NCT00253253	Not specified	COMPLETED	Long-Term Outcome in Congenital Undescended Testis After Surgical Treatment by Orchidopexy
NCT00264121	Not specified	UNKNOWN	The Incidence of Congenital Undescended Testis Among Dutch Infants
NCT00435383	Not specified	COMPLETED	Comparing Oxygen Saturation in Post Anesthesia Care Unit After Different Methods of Pain Relief
NCT00565513	Not specified	COMPLETED	Cryptorchidism: Impact of in Utero Exposure to Xenobiotics With Hormonal Action
NCT01604915	Not specified	COMPLETED	Comparison of Dexamethasone Added to Ropivacaine and Ropivacaine Alone in Caudal Analgesia in Children Undergoing Orchiopexy
NCT01896076	Not specified	COMPLETED	The Caudal Space in Children: Ultrasound Evaluation
NCT02040389	Not specified	COMPLETED	Visual Guidelines and Tutoring in Pediatric Urological Surgery
NCT02249637	Not specified	COMPLETED	A Novel Technique of Circumcision Incision Orchidopexy
NCT02731989	Not specified	UNKNOWN	Comparison Between the Clinical Assessment of the Undescended Testis and Its’ Ultrasonographic Size
NCT02936024	Not specified	UNKNOWN	One Stage vs. Two Stage Gubernaculum Sparing Laparoscopic Orchidopexy (GSLO)
NCT03575377	Not specified	COMPLETED	Opioid Use, Storage, and Disposal Among Pediatric Patients After Surgery
NCT03677453	Not specified	COMPLETED	Interactive Perioperative Teaching Platform (IPTP)
NCT04342026	Not specified	RECRUITING	Role of the Environment and Endocrine Disruptors in Child Cryptorchidism
NCT04528381	Not specified	UNKNOWN	Role of Laparoscopy in Management of Non-palpable Undescended Testis : Assuit University Experience
NCT05097820	Not specified	RECRUITING	Prospective Observational Study on SEBBIN Silicone Gel-filled Testicular Implants
NCT05558748	Not specified	UNKNOWN	Comparison of USG-Guided Caudal Versus Ilioinguinal/Iliohypogastric Nerve Block for Pediatric Inguinal Surgeries
NCT06187844	Not specified	UNKNOWN	Value of Inguinal Exploration for Impalpable Testes
NCT06533306	Not specified	COMPLETED	Metachronous Acquired Contralateral Cryptorchidism in Patients With a History of Unilateral Cryptorchidism.
NCT06558994	Not specified	RECRUITING	Transection Versus Ligation of Internal Spermatic Vessels in Laparoscopic Fowler-Stephens Orchidopexy
NCT06560086	Not specified	UNKNOWN	Ketoconazole Contributes to Cryptorchidism Outcome Via Modulating Macrophage Trem2
NCT06698081	Not specified	RECRUITING	The Effect of Using Multimedia During the Informed Consent Process on the Anxiety of Parents of Orchiopexy Patients
NCT06862258	Not specified	NOT_YET_RECRUITING	Shehata Technique in the Treatment of Intra-abdominal Testis
NCT07106502	Not specified	NOT_YET_RECRUITING	Learning to Palpate the Child’s Testicles Using Simulation
NCT07233265	Not specified	RECRUITING	Comparison of Single Incision Scrotal vs Standard Two Incision Inguinal Orchidopexy in Children Under 10 Years.
NCT07315737	Not specified	COMPLETED	Could miRNAs be Used as Markers for Distinguishing Undescended Testicles From Retractile Testicles
NCT07319637	Not specified	COMPLETED	Comparing Two Types of Surgery for Children With Undescended Testicles When the Hernia Sac Is Tied or Not
NCT07426796	Not specified	RECRUITING	Comparison of Posterior QLB and QIPB in Pediatric Undescended Testis Surgery.
NCT07586332	Not specified	ACTIVE_NOT_RECRUITING	INVESTIGATION OF THE GENETIC ETIOLOGY OF HERNIA SAC DEVELOPMENT IN MALE CHILDREN WITH UNDESCENDED TESTIS AND INGUINAL HERNIA
NCT00485186	Not specified	WITHDRAWN	Gene Polymorphisms Influencing Steroid Synthesis and Action
NCT01875640	Not specified	COMPLETED	Decision Support for Parents Receiving Information About Child’s Rare Disease
NCT02784184	Not specified	UNKNOWN	COPENHAGEN Minipuberty Study
NCT03102554	Not specified	ENROLLING_BY_INVITATION	Genetics of Differences of Sex Development and Hypospadias
NCT03283852	Not specified	RECRUITING	Identifying New Genetic Causes to Development Disorders
NCT04195490	Not specified	UNKNOWN	Evaluation of Outcomes of Feminizing Genitoplasty in Children With Disorders of Sex Development
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes
NCT04717349	Not specified	RECRUITING	Data Collection Study of Pediatric and Adolescent Gynecology Conditions