LHCGR

Summary

LHCGR (luteinizing hormone/choriogonadotropin receptor, HGNC:6585) is a protein-coding gene on chromosome 2p16.3, encoding Lutropin-choriogonadotropic hormone receptor (P22888). Receptor for lutropin-choriogonadotropic hormone.

This gene encodes the receptor for both luteinizing hormone and choriogonadotropin. This receptor belongs to the G-protein coupled receptor 1 family, and its activity is mediated by G proteins which activate adenylate cyclase. Mutations in this gene result in disorders of male secondary sexual character development, including familial male precocious puberty, also known as testotoxicosis, hypogonadotropic hypogonadism, Leydig cell adenoma with precocious puberty, and male pseudohermaphtoditism with Leydig cell hypoplasia.

Source: NCBI Gene 3973 — RefSeq curated summary.

At a glance

• Gene–disease (curated): familial male-limited precocious puberty (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 19
• Clinical variants (ClinVar): 262 total — 24 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 17
• Druggable target: yes
• MANE Select transcript: NM_000233

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6585
Approved symbol	LHCGR
Name	luteinizing hormone/choriogonadotropin receptor
Location	2p16.3
Locus type	gene with protein product
Status	Approved
Aliases	LHR, LCGR, LGR2, ULG5
Ensembl gene	ENSG00000138039
Ensembl biotype	protein_coding
OMIM	152790
Entrez	3973

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000294954, ENST00000401907, ENST00000403273, ENST00000405626, ENST00000428232, ENST00000477576, ENST00000913067

RefSeq mRNA: 1 — MANE Select: NM_000233 NM_000233

CCDS: CCDS1842

Canonical transcript exons

ENST00000294954 — 11 exons

Exon	Start	End
ENSE00000809863	48698615	48698800
ENSE00001069335	48729153	48729227
ENSE00001894530	48755511	48755724
ENSE00001925227	48686774	48688849
ENSE00003480129	48694224	48694304
ENSE00003755458	48713986	48714054
ENSE00003755663	48723456	48723533
ENSE00003755921	48723622	48723696
ENSE00003758052	48708948	48709022
ENSE00003758714	48731227	48731298
ENSE00003759177	48725676	48725750

Expression profiles

Bgee: expression breadth ubiquitous, 123 present calls, max score 86.92.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3158 / max 33.6196, expressed in 126 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
28249	0.2170	92
28250	0.0988	50

Top tissues by expression

276 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	86.92	gold quality
sural nerve	UBERON:0015488	79.60	gold quality
lower esophagus muscularis layer	UBERON:0035833	74.86	gold quality
lower esophagus	UBERON:0013473	74.80	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	72.97	gold quality
tibial nerve	UBERON:0001323	71.05	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	66.23	gold quality
calcaneal tendon	UBERON:0003701	66.01	gold quality
left ovary	UBERON:0002119	64.07	gold quality
colonic epithelium	UBERON:0000397	62.78	silver quality
right ovary	UBERON:0002118	62.47	gold quality
lower esophagus mucosa	UBERON:0035834	61.52	gold quality
adipose tissue	UBERON:0001013	60.94	gold quality
ovary	UBERON:0000992	60.50	gold quality
connective tissue	UBERON:0002384	60.31	gold quality
stromal cell of endometrium	CL:0002255	60.01	gold quality
esophagus	UBERON:0001043	59.47	gold quality
subcutaneous adipose tissue	UBERON:0002190	59.14	gold quality
adrenal tissue	UBERON:0018303	58.93	gold quality
adipose tissue of abdominal region	UBERON:0007808	57.40	gold quality
omental fat pad	UBERON:0010414	57.22	gold quality
peritoneum	UBERON:0002358	57.17	gold quality
tendon	UBERON:0000043	56.25	gold quality
trigeminal ganglion	UBERON:0001675	56.12	silver quality
endometrium epithelium	UBERON:0004811	56.00	gold quality
cranial nerve II	UBERON:0000941	55.70	silver quality
buccal mucosa cell	CL:0002336	55.00	silver quality
skin of hip	UBERON:0001554	52.33	silver quality
right adrenal gland	UBERON:0001233	51.66	gold quality
urinary bladder	UBERON:0001255	51.25	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.73

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EGR1, NR2C2, NR2F1, NR2F2, NR2F6, NR5A1, PGR, SP1, SP3, TBX15, TCF3

Literature-anchored findings (GeneRIF, showing 40)

• Results confirm the fact that somatic activating mutations of gonadotropin receptors are involved in gonadal tumorigenesis. (PMID:11857565)
• review of the mechanism of desensitization to LH mediated by extensive clustering and internalization of the LH hormone-receptor complex (PMID:11988313)
• Cis- and trans-activation of hormone receptors: the LH receptor (PMID:12040016)
• Evidence that luteinising hormone receptor polymorphisms may contribute to male undermasculinisation. (PMID:12088926)
• HDAC-Sin3A complex regulates LHR Gene transcription (PMID:12091390)
• study of the conformations of the active and inactive states of the hLHR (PMID:12242044)
• LH receptor gene expresses in normal endometrium at very low levels, and at increased levels in endometrial cancerous tissues compared with surrounding microscopically normal tissues (PMID:12270268)
• Homozygous mutation within the conserved Ala-Phe-Asn-Glu-Thr motif of exon 7 of the LH receptor causes male pseudohermaphroditism. (PMID:12444891)
• Structure of LH receptor based on molecular modeling and the supporting experimental data from engineered and naturally occurring mutations. (review) (PMID:12450321)
• LH-responsive Cushing’s syndrome, associated with bilateral adrenal hyperplasia, may result from aberrant (or possibly increased) adrenal LH receptor expression. (PMID:12519858)
• findings suggest that the luteinizing hormone receptor 18insLQ gene polymorphism determines an earlier age of disease onset and is prognostic for poor outcome of breast cancer (PMID:12679452)
• although exon 10 of the luteinizing hormone receptor plays no role in ligand binding, it is important for receptor activation by LH by a mechanism probably involving extracellular conformational changes (PMID:12727981)
• Point mutations in the hinge region or ligand binding could cause conformational changes in the transmembrane region that result in Gs activation. (PMID:12770743)
• In human ovaries, MAb found 6 distinct LHR bands migrating at approximately 92, 80, 68, 59, 52 & 48 kDa. There is a possible role for LHR in the development of abnormal pregnancy, pelvic floor disorders & Alzheimer’s disease. (PMID:12816543)
• human cervix contains functional LH/hCG receptors, which suggests that LH during the menstrual cycle and hCG during pregnancy may regulate cervical functions. (PMID:12843195)
• results of mutagenesis and buffer studies suggest that electrostatic effects contribute to ligand binding and/or that the LHR ectodomain may exist in two conformations, one being more accessible to ligand at reduced ionic strength. (PMID:12850276)
• the G proteins activated by constitutively active mutants of the hLHR associated with Leydig cell hyperplasia or tumors are identical and are the same as those activated by the agonist-engaged hLHR-wt. (PMID:12933660)
• The LHR gene promoter is repressed by cross talk among the transcription factors EAR3, SP1 and TFIIB. (PMID:12972613)
• characterization of interaction with GAIP-interacting protein C terminus (PMID:14507927)
• cell surface human lutropin receptor self-associates (PMID:14594799)
• a novel, noncontiguous, transferable motif that participates in the sorting of internalized G protein-coupled receptors (PMID:14605099)
• Fetal kidney, liver, pancreas, lung, small and large intestines, and adrenals contained hCG/LH receptors. May mediate pleiotropic actions of hCG in growing human fetus. (PMID:14764820)
• analysis of mutations in human luteinizing hormone receptor (PMID:15016840)
• splice variant of the human luteinizing hormone (LH) receptor modulates the expression of wild-type human LH receptor (PMID:15031322)
• H295R cells contain LH/hCG receptors, which are coupled to increasing DHEAS secretion through upregulating the dhea sulfotransferase enzyme mRNA level (PMID:15084485)
• These data do not support the hypothesis that qualitative changes in LH receptor splicing have a role in luteolysis or that a naturally occurring LH receptor lacking exon 10 has a role in maternal recognition of pregnancy. (PMID:15169923)
• demonstrated the presence of LH/hCG receptor mRNA and protein in normal male breast tissue obtained at autopsy and archival samples of benign gynecomastia and male breast carcinoma (PMID:15292356)
• characterization of the position of conserved alpha-subunit regions in lutropin receptor complexes (PMID:15304492)
• contacts between the small seatbelt loop of alpha-human choriogonadotropin and the lutropin receptor involve its backbone atoms and possibly the side chain of residue betaAsp-99 (PMID:15304512)
• palmitoylation of cysteine residues 643 and 644 of the human LHR is a determinant of recycling (PMID:15539429)
• Leydig cell hypoplasia due to inactivation of luteinizing hormone receptor by a novel homozygous nonsense truncation mutation in the seventh transmembrane domain (PMID:15607529)
• SP factors play an intimate part in transcriptional regulation of the this receptor gene. (PMID:15788387)
• activation of the LHR results from subtle modifications of intramolecular interactions between the two domains and low-affinity binding of hCG to the extracellular loops or residues preceding the first transmembrane segment (PMID:15878956)
• Lutropin receptors form homo- and heterodimers, via interactions involving primarily their heptahelical domains. The large hormone-binding ectodomains were dispensable for dimerization but modulated protomer interaction. The dimers show allosterism. (PMID:15889138)
• human follitropin (FSH) receptor association with splicing variant of human lutropin/choriogonadotropin receptor negatively controls the expression of human FSH receptor (PMID:15890674)
• the structural trigger of the constitutive activity of the L457R mutant of the lutropin receptor may also be responsible for its lack of hormone responsiveness (PMID:15908694)
• Epigenetic silencing and activation of the LHR gene is achieved through coordinated histone acetylation and promoter DNA methylation. (PMID:16135786)
• LH receptor expression is elevated in aldosterone-producing adenomas, which makes LH a potential cause of the excessive production of aldosterone in a subset of these adrenal tumors. (PMID:16332935)
• LHR I114F mutation reduces ligand binding and signal transduction, and is partially responsible for Leydig cell hypoplasia (PMID:16709601)
• Decidualization results in the downregulation of LHCGR. (PMID:16837644)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	lhcgr	ENSDARG00000026081
mus_musculus	Lhcgr	ENSMUSG00000024107
rattus_norvegicus	Lhcgr	ENSRNOG00000016712
drosophila_melanogaster	Lgr1	FBGN0016650
caenorhabditis_elegans		WBGENE00008239

Paralogs (2): TSHR (ENSG00000165409), FSHR (ENSG00000170820)

Protein

Protein identifiers

Lutropin-choriogonadotropic hormone receptor — P22888 (reviewed: P22888)

Alternative names: Luteinizing hormone receptor

All UniProt accessions (5): P22888, E7ENI1, E7EQB5, E7ESK4, H7C226

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for lutropin-choriogonadotropic hormone. The activity of this receptor is mediated by G proteins which activate adenylate cyclase.

Subcellular location. Cell membrane.

Tissue specificity. Gonadal and thyroid cells.

Post-translational modifications. Sulfated.

Disease relevance. Familial male precocious puberty (FMPP) [MIM:176410] In FMPP the receptor is constitutively activated. The disease is caused by variants affecting the gene represented in this entry. Luteinizing hormone resistance (LHR) [MIM:238320] An autosomal recessive disorder characterized by unresponsiveness to luteinizing hormone, defective sexual development in males, and defective follicular development and ovulation, amenorrhea and infertility in females. Two forms of the disorder have been defined in males. Type 1 is a severe form characterized by complete 46,XY male pseudohermaphroditism, low testosterone and high luteinizing hormone levels, total lack of responsiveness to luteinizing and chorionic gonadotropin hormones, lack of breast development, and absent development of secondary male sex characteristics. Type 2, a milder form, displays a broader range of phenotypic expression ranging from micropenis to severe hypospadias. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the G-protein coupled receptor 1 family. FSH/LSH/TSH subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P22888-1	Long	yes
P22888-2	Short

RefSeq proteins (1): NP_000224* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR002131	Gphrmn_rcpt_fam	Family
IPR002273	LSH_rcpt	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain
IPR026906	LRR_5	Repeat
IPR032675	LRR_dom_sf	Homologous_superfamily

Pfam: PF00001, PF13306

UniProt features (123 total): sequence variant 33, strand 15, helix 15, sequence conflict 14, topological domain 8, transmembrane region 7, turn 7, repeat 6, glycosylation site 6, mutagenesis site 4, lipid moiety-binding region 2, signal peptide 1, chain 1, domain 1, modified residue 1, disulfide bond 1, splice variant 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
7FIH	ELECTRON MICROSCOPY	3.2
7FIJ	ELECTRON MICROSCOPY	3.8
7FIG	ELECTRON MICROSCOPY	3.9
7FII	ELECTRON MICROSCOPY	4.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P22888-F1	79.95	0.48

Antibody-complex structures (SAbDab): 1 — 7FIG

Functional residue map

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

Post-translational modifications (3): 331, 643, 644

Disulfide bonds (1): 439–514

Glycosylation sites (6): 99, 174, 195, 291, 299, 313

Mutagenesis-validated functional residues (4):

Position	Phenotype
331	reduces intracellular camp accumulation.
333	no change in intracellular camp accumulation.
643	loss of palmitoylation.
644	loss of palmitoylation.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-375281	Hormone ligand-binding receptors
R-HSA-418555	G alpha (s) signalling events
R-HSA-162582	Signal Transduction
R-HSA-372790	Signaling by GPCR
R-HSA-373076	Class A/1 (Rhodopsin-like receptors)
R-HSA-388396	GPCR downstream signalling
R-HSA-500792	GPCR ligand binding

MSigDB gene sets: 222 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_COGNITION, GOBP_MALE_GENITALIA_DEVELOPMENT, GOBP_INOSITOL_PHOSPHATE_METABOLIC_PROCESS, GOBP_POLYOL_METABOLIC_PROCESS, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_MALE_GAMETE_GENERATION, GOBP_POSITIVE_REGULATION_OF_ALCOHOL_BIOSYNTHETIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CARBOHYDRATE_METABOLIC_PROCESS, GOBP_REGULATION_OF_LIPID_BIOSYNTHETIC_PROCESS, BROWNE_HCMV_INFECTION_48HR_DN, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY

GO Biological Process (23): ovarian follicle development (GO:0001541), G protein-coupled receptor signaling pathway (GO:0007186), G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger (GO:0007187), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), phospholipase C-activating G protein-coupled receptor signaling pathway (GO:0007200), spermatogenesis (GO:0007283), male gonad development (GO:0008584), hormone-mediated signaling pathway (GO:0009755), ovulation cycle process (GO:0022602), male genitalia development (GO:0030539), positive regulation of inositol trisphosphate biosynthetic process (GO:0032962), luteinizing hormone signaling pathway (GO:0042700), development of animal secondary male sexual characteristics (GO:0046544), cognition (GO:0050890), uterus development (GO:0060065), cellular response to gonadotropin stimulus (GO:0071371), cellular response to luteinizing hormone stimulus (GO:0071373), seminiferous tubule development (GO:0072520), regulation of steroid hormone biosynthetic process (GO:0090030), signal transduction (GO:0007165), female gonad development (GO:0008585), cellular response to hormone stimulus (GO:0032870), response to gonadotropin (GO:0034698)

GO Molecular Function (7): luteinizing hormone receptor activity (GO:0004964), G protein-coupled peptide receptor activity (GO:0008528), choriogonadotropin hormone receptor activity (GO:0035472), choriogonadotropin hormone binding (GO:0038106), G protein-coupled receptor activity (GO:0004930), protein-hormone receptor activity (GO:0016500), signaling receptor activity (GO:0038023)

GO Cellular Component (4): endosome (GO:0005768), plasma membrane (GO:0005886), centriolar satellite (GO:0034451), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
G protein-coupled receptor activity	4
G protein-coupled receptor signaling pathway	4
signal transduction	2
cellular response to hormone stimulus	2
male sex differentiation	2
reproductive structure development	2
protein-hormone receptor activity	2
cellular anatomical structure	2
female gonad development	1
anatomical structure development	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
phospholipase C activator activity	1
developmental process involved in reproduction	1
male gamete generation	1
gonad development	1
development of primary male sexual characteristics	1
reproductive process	1
ovulation cycle	1
rhythmic process	1
genitalia development	1
reproductive system development	1
inositol trisphosphate biosynthetic process	1
regulation of inositol trisphosphate biosynthetic process	1
positive regulation of inositol phosphate biosynthetic process	1
development of animal secondary sexual characteristics	1
nervous system process	1
animal organ development	1
response to gonadotropin	1
response to luteinizing hormone	1
cellular response to gonadotropin stimulus	1
cellular response to peptide hormone stimulus	1
male gonad development	1
tube development	1
regulation of hormone biosynthetic process	1
regulation of steroid biosynthetic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1

Protein interactions and networks

STRING

1490 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LHCGR	FSHB	P01225	896
LHCGR	CYP11A1	P05108	853
LHCGR	CYP17A1	P05093	817
LHCGR	HSD3B1	P14060	809
LHCGR	CYP19A1	P11511	782
LHCGR	BTC	P35070	780
LHCGR	GNRH1	P01148	774
LHCGR	GDF9	O60383	774
LHCGR	EREG	O14944	767
LHCGR	AREG	P15514	766
LHCGR	HSF2	Q03933	764
LHCGR	HSD17B3	P37058	761
LHCGR	STAR	P49675	754
LHCGR	BMP15	O95972	741
LHCGR	INSL3	P51460	741

IntAct

5 interactions, top by confidence:

A	B	Type	Score
LHCGR	LHCGR	psi-mi:“MI:0915”(physical association)	0.460
LHCGR	LHCGR	psi-mi:“MI:0403”(colocalization)	0.460
LHCGR	FURIN	psi-mi:“MI:0914”(association)	0.350
GPER1	LHCGR	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (11): GIPC1 (Two-hybrid), LHCGR (Reconstituted Complex), GIPC1 (Affinity Capture-Western), CGA (Affinity Capture-Western), ARRB2 (Reconstituted Complex), FURIN (Affinity Capture-MS), DNAJC18 (Affinity Capture-MS), PITPNA (Affinity Capture-MS), LHCGR (Affinity Capture-MS), LHCGR (Affinity Capture-MS), LHCGR (Affinity Capture-MS)

ESM2 similar proteins: A4IIW9, B2LT61, B2LT62, B2LT64, B2LT65, B3Y613, B3Y614, B3Y615, B3Y618, B5T267, O60602, O60603, P16235, P16582, P22888, P30730, P58681, P58682, Q0GC71, Q0ZUL9, Q15399, Q2PZH4, Q2V897, Q3URE9, Q5M8M9, Q5RDJ4, Q66HV9, Q689D1, Q6GV17, Q6T752, Q704V6, Q7L985, Q8CBC6, Q8N7C0, Q95LA9, Q95M53, Q96FE5, Q9BXR5, Q9D1T0, Q9DD78

Diamond homologs: O02721, P14763, P16235, P16473, P16582, P20395, P21463, P22888, P23945, P30549, P30730, P32212, P35376, P35378, P35379, P35409, P46023, P47750, P47799, P49059, P56495, P79763, Q27987, Q28005, Q28585, Q5GJ04, Q6QMG1, Q6R6L8, Q6YNB6, Q7ZTV5, Q8R428, Q8SPP9, Q90674, Q95179, Q9BGN4, Q9EQD2, B0BLW3, O42328, O42451, O42466

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
Goserelin	“up-regulates activity”	LHCGR	“chemical activation”
“CGB Family”	up-regulates	LHCGR	binding
LHB	up-regulates	LHCGR	binding
NR2F6	“down-regulates quantity by repression”	LHCGR	“transcriptional regulation”
NR2C2	“up-regulates quantity by expression”	LHCGR	“transcriptional regulation”
NR2F1	“down-regulates quantity by repression”	LHCGR	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	24
Likely pathogenic	9
Uncertain significance	126
Likely benign	37
Benign	39

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1338265	NM_000233.4(LHCGR):c.35_36insCA (p.Lys12fs)	Pathogenic
1389006	NM_000233.4(LHCGR):c.1713G>T (p.Met571Ile)	Pathogenic
14387	NM_000233.4(LHCGR):c.1627T>C (p.Cys543Arg)	Pathogenic
14389	NM_000233.4(LHCGR):c.1730C>T (p.Thr577Ile)	Pathogenic
14396	NM_000233.4(LHCGR):c.391T>C (p.Cys131Arg)	Pathogenic
14398	NM_000233.4(LHCGR):c.1060G>A (p.Glu354Lys)	Pathogenic
14399	NM_000233.4(LHCGR):c.1824_1829del (p.Val609_Leu610del)	Pathogenic
14400	NM_000233.4(LHCGR):c.1874T>A (p.Ile625Lys)	Pathogenic
14402	NM_000233.4(LHCGR):c.1624A>C (p.Ile542Leu)	Pathogenic
14403	NM_000233.4(LHCGR):c.1732G>C (p.Asp578His)	Pathogenic
14404	NM_000233.4(LHCGR):c.866+1515_948-2168del	Pathogenic
14405	NM_000233.4(LHCGR):c.55_56insTGCTGAAGCTGCTGCTGCTGCTGCAGCTGCAGC (p.Gln18_Pro19insLeuLeuLysLeuLeuLeuLeuLeuGlnLeuGln)	Pathogenic
14406	NM_000233.4(LHCGR):c.1103T>C (p.Leu368Pro)	Pathogenic
14409	NM_000233.4(LHCGR):c.1027T>A (p.Cys343Ser)	Pathogenic
14410	NM_000233.4(LHCGR):c.1505T>C (p.Leu502Pro)	Pathogenic
14412	NM_000233.4(LHCGR):c.1691A>G (p.Asp564Gly)	Pathogenic
3656021	NM_000233.4(LHCGR):c.220G>T (p.Glu74Ter)	Pathogenic
3661165	NM_000233.4(LHCGR):c.1111_1112dup (p.Leu372fs)	Pathogenic
4727123	NM_000233.4(LHCGR):c.947+1G>C	Pathogenic
4796674	NM_000233.4(LHCGR):c.384-2A>G	Pathogenic
492758	NM_000233.4(LHCGR):c.580T>G (p.Phe194Val)	Pathogenic
626211	NM_000233.4(LHCGR):c.442G>T (p.Glu148Ter)	Pathogenic
804990	NM_000233.4(LHCGR):c.1723A>C (p.Ile575Leu)	Pathogenic
996742	NM_000233.4(LHCGR):c.537-1G>T	Pathogenic
1184482	NM_000233.4(LHCGR):c.1573C>T (p.Gln525Ter)	Likely pathogenic
14397	NM_000233.4(LHCGR):c.1118C>T (p.Ala373Val)	Likely pathogenic
2004397	NM_000233.4(LHCGR):c.1178T>G (p.Val393Gly)	Likely pathogenic
2633361	NM_000233.4(LHCGR):c.29T>C (p.Leu10Pro)	Likely pathogenic
2633438	NM_000233.4(LHCGR):c.32T>C (p.Leu11Pro)	Likely pathogenic
3586722	NM_000233.4(LHCGR):c.1786del (p.Val596fs)	Likely pathogenic

SpliceAI

2467 predictions. Top by Δscore:

Variant	Effect	Δscore
2:48725674:A:AC	donor_gain	1.0000
2:48725675:C:CC	donor_gain	1.0000
2:48731225:A:AC	donor_gain	1.0000
2:48731226:C:CC	donor_gain	1.0000
2:48755505:ACTC:A	donor_loss	1.0000
2:48755507:TCA:T	donor_loss	1.0000
2:48755508:CACAG:C	donor_loss	1.0000
2:48755509:A:AC	donor_gain	1.0000
2:48755509:A:T	donor_loss	1.0000
2:48755509:AC:A	donor_loss	1.0000
2:48755509:ACAGT:A	donor_gain	1.0000
2:48755510:C:CC	donor_gain	1.0000
2:48755510:CA:C	donor_gain	1.0000
2:48755510:CAG:C	donor_gain	1.0000
2:48755510:CAGT:C	donor_gain	1.0000
2:48755510:CAGTC:C	donor_gain	1.0000
2:48708946:A:AC	donor_gain	0.9900
2:48708947:C:CC	donor_gain	0.9900
2:48708947:CAA:C	donor_gain	0.9900
2:48708947:CAAG:C	donor_gain	0.9900
2:48709019:CTCC:C	acceptor_gain	0.9900
2:48709021:CC:C	acceptor_gain	0.9900
2:48709022:CC:C	acceptor_gain	0.9900
2:48709022:CCT:C	acceptor_loss	0.9900
2:48709024:T:A	acceptor_loss	0.9900
2:48713984:A:AC	donor_gain	0.9900
2:48713985:C:CC	donor_gain	0.9900
2:48713985:C:CG	donor_gain	0.9900
2:48713985:CA:C	donor_gain	0.9900
2:48714055:C:CC	acceptor_gain	0.9900

AlphaMissense

4568 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:48688498:C:A	W433C	0.994
2:48688498:C:G	W433C	0.994
2:48698738:A:G	L248P	0.992
2:48723518:G:C	N158K	0.992
2:48723518:G:T	N158K	0.992
2:48688255:G:C	C514W	0.990
2:48688257:A:G	C514R	0.990
2:48713986:A:G	L202P	0.990
2:48725685:A:G	L125S	0.990
2:48714010:A:G	F194S	0.988
2:48688256:C:T	C514Y	0.987
2:48688500:A:G	W433R	0.987
2:48688500:A:T	W433R	0.987
2:48688481:C:G	C439S	0.985
2:48688482:A:T	C439S	0.985
2:48709007:G:C	N207K	0.985
2:48709007:G:T	N207K	0.985
2:48714039:A:C	N184K	0.985
2:48714039:A:T	N184K	0.985
2:48725703:A:G	F119S	0.985
2:48729162:A:C	L100W	0.985
2:48688261:A:C	S512R	0.984
2:48688261:A:T	S512R	0.984
2:48688263:T:G	S512R	0.984
2:48729180:A:C	F94C	0.984
2:48688442:A:G	L452P	0.983
2:48688769:C:G	C343S	0.983
2:48688770:A:T	C343S	0.983
2:48698732:G:T	A250D	0.983
2:48709017:A:G	L204P	0.983

dbSNP variants (sampled 300 via entrez): RS1000038594 (2:48707349 C>T), RS1000056159 (2:48697004 G>A), RS1000069966 (2:48740937 C>A), RS1000128461 (2:48731769 CA>C), RS1000152885 (2:48752310 C>G,T), RS1000159388 (2:48728356 T>A), RS1000272579 (2:48693609 C>T), RS1000274992 (2:48726397 A>C,G), RS1000281631 (2:48726562 C>A,G,T), RS1000286938 (2:48715847 T>C), RS1000296179 (2:48728149 A>G), RS1000320833 (2:48717994 C>A,G), RS1000338663 (2:48716140 C>A,G), RS1000342078 (2:48750818 C>G), RS1000427399 (2:48688272 T>C)

Disease associations

OMIM: gene MIM:152790 | disease phenotypes: MIM:238320, MIM:176410

GenCC curated gene-disease

Disease	Classification	Inheritance
familial male-limited precocious puberty	Strong	Autosomal dominant
Leydig cell hypoplasia, type 1	Strong	Autosomal recessive

Mondo (5): Leydig cell hypoplasia, type 1 (MONDO:0009384), familial male-limited precocious puberty (MONDO:0008303), disorder of sexual differentiation (MONDO:0002145), 46 XY differences of sex development (MONDO:0020040), pseudohermaphroditism (MONDO:0005518)

Orphanet (3): Familial peripheral male-limited precocious puberty (Orphanet:3000), Difference of sex development (Orphanet:90771), 46,XY difference of sex development (Orphanet:98085)

HPO phenotypes

17 total (17 of 17 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000040	Long penis
HP:0000053	Macroorchidism
HP:0000098	Tall stature
HP:0000708	Atypical behavior
HP:0000798	Oligozoospermia
HP:0000815	Hypergonadotropic hypogonadism
HP:0000826	Precocious puberty
HP:0000837	Increased circulating gonadotropin level
HP:0001061	Acne
HP:0001470	Sex-limited expression
HP:0001595	Abnormal hair morphology
HP:0003251	Male infertility
HP:0005616	Accelerated skeletal maturation
HP:0007018	Attention deficit hyperactivity disorder
HP:0008185	Precocious puberty in males
HP:0008734	Decreased testicular size

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST000914_4	Polycystic ovary syndrome	8.000000e-21
GCST001612_15	Sex hormone-binding globulin levels	1.000000e-07
GCST001634_3	Polycystic ovary syndrome	4.000000e-09
GCST004813_1	Laterality in neovascular age-related macular degeneration	3.000000e-08
GCST004904_147	Body mass index	2.000000e-08
GCST010173_88	Triglyceride levels	2.000000e-10
GCST90020024_865	A body shape index	2.000000e-09
GCST90020024_866	A body shape index	3.000000e-08
GCST90020025_1601	Waist-to-hip ratio adjusted for BMI	2.000000e-11
GCST90020025_1603	Waist-to-hip ratio adjusted for BMI	4.000000e-17
GCST90020025_1604	Waist-to-hip ratio adjusted for BMI	8.000000e-12
GCST90020025_1605	Waist-to-hip ratio adjusted for BMI	6.000000e-11
GCST90020025_1606	Waist-to-hip ratio adjusted for BMI	6.000000e-09
GCST90020027_45	Waist-hip index	7.000000e-12
GCST90020027_47	Waist-hip index	9.000000e-17
GCST90020027_48	Waist-hip index	2.000000e-11
GCST90020027_49	Waist-hip index	2.000000e-10
GCST90020027_50	Waist-hip index	2.000000e-08
GCST90020028_28	Hip circumference adjusted for BMI	3.000000e-09

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004696	sex hormone-binding globulin measurement
EFO:0008372	laterality measurement
EFO:0004340	body mass index
EFO:0004530	triglyceride measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D058490	Disorder of Sex Development, 46,XY	C12.050.351.875.253.096; C12.200.706.316.096; C12.800.316.096; C16.131.939.316.096; C19.391.119.096
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): CHEMBL1854 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: gpcr — Glycoprotein hormone receptors

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
hCG	Full agonist	11.8	pKd
LH	Full agonist	10.9	pIC50

ChEMBL bioactivities

74 potent at pChembl≥5 of 76 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.51	Ki	0.311	nM	CHEMBL246321
9.00	EC50	1	nM	CHEMBL1651721
8.30	EC50	5	nM	CHEMBL1651828
8.00	EC50	10	nM	CHEMBL1651723
7.70	EC50	20	nM	CHEMBL246321
7.62	EC50	24	nM	CHEMBL1651829
7.57	EC50	27	nM	CHEMBL1651823
7.41	EC50	39	nM	CHEMBL1651831
7.37	EC50	43	nM	CHEMBL1651824
7.26	EC50	55	nM	CHEMBL1651826
7.24	EC50	57	nM	CHEMBL1651822
7.21	EC50	61	nM	CHEMBL1651825
7.12	EC50	75	nM	CHEMBL1651821
7.10	EC50	80	nM	CHEMBL429108
7.10	EC50	80	nM	CHEMBL1651830
7.09	IC50	81	nM	CHEMBL4460075
7.02	IC50	96	nM	CHEMBL4537998
7.02	IC50	95	nM	CHEMBL2032175
7.01	IC50	97	nM	CHEMBL4537998
6.99	IC50	102	nM	CHEMBL4587440
6.97	IC50	107	nM	CHEMBL4573509
6.90	IC50	127	nM	CHEMBL4531781
6.82	EC50	150	nM	CHEMBL439392
6.77	EC50	170	nM	CHEMBL247700
6.76	IC50	174	nM	CHEMBL4443605
6.73	IC50	185	nM	BAY-899
6.72	EC50	190	nM	CHEMBL393847
6.71	IC50	193	nM	CHEMBL4461980
6.70	IC50	200	nM	CHEMBL4537998
6.68	IC50	207	nM	CHEMBL4522381
6.66	EC50	220	nM	CHEMBL211405
6.60	EC50	250	nM	CHEMBL397316
6.56	IC50	275	nM	CHEMBL4581889
6.52	EC50	300	nM	CHEMBL211405
6.51	IC50	312	nM	CHEMBL4555151
6.48	IC50	332	nM	CHEMBL4579421
6.46	EC50	350	nM	CHEMBL211405
6.42	IC50	378	nM	CHEMBL4593222
6.39	IC50	403	nM	CHEMBL4471621
6.32	EC50	480	nM	CHEMBL1703522
6.31	IC50	486	nM	CHEMBL4590976
6.30	EC50	500	nM	CHEMBL247945
6.24	IC50	580	nM	CHEMBL4580951
6.19	IC50	650	nM	CHEMBL4537998
6.10	EC50	800	nM	CHEMBL377769
6.10	EC50	800	nM	CHEMBL377399
5.96	EC50	1100	nM	CHEMBL211871
5.92	EC50	1200	nM	CHEMBL212815
5.92	IC50	1200	nM	CHEMBL4537998
5.82	EC50	1500	nM	CHEMBL211129

PubChem BioAssay actives

72 with measured affinity, of 223 total; 50 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
N-[(2S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]-5-[1-(4-tert-butylphenyl)-3-pyridin-3-ylpyrazol-5-yl]pentanamide	306716: Displacement of [125I]hCG from LH receptor	ki	0.0003	uM
5-amino-N-tert-butyl-2-methylsulfanyl-4-[3-[[2-oxo-2-(prop-2-ynylamino)ethyl]amino]phenyl]thieno[2,3-d]pyrimidine-6-carboxamide	553581: Agonist activity at human LH receptor expressed in CHO-K1 cells assessed as stimulation of luciferase activity by CRE-driven luciferase reporter gene assay	ec50	0.0010	uM
5-amino-4-[3-[[2-[[1-[2-[2-(2-azidoethoxy)ethoxy]ethyl]triazol-4-yl]methylamino]-2-oxoethyl]amino]phenyl]-N-tert-butyl-2-methylsulfanylthieno[2,3-d]pyrimidine-6-carboxamide	553581: Agonist activity at human LH receptor expressed in CHO-K1 cells assessed as stimulation of luciferase activity by CRE-driven luciferase reporter gene assay	ec50	0.0050	uM
4-[3-[[2-[[1-[2-[4-[[4-[(4R)-1-acetyl-2,2,4-trimethyl-6-[(4-phenylbenzoyl)amino]-3H-quinolin-4-yl]phenoxy]methyl]triazol-1-yl]ethyl]triazol-4-yl]methylamino]-2-oxoethyl]amino]phenyl]-5-amino-N-tert-butyl-2-methylsulfanylthieno[2,3-d]pyrimidine-6-carboxamide	553581: Agonist activity at human LH receptor expressed in CHO-K1 cells assessed as stimulation of luciferase activity by CRE-driven luciferase reporter gene assay	ec50	0.0100	uM
4-[3-[[2-[[1-[2-[4-[[4-[(4S)-1-acetyl-2,2,4-trimethyl-6-[(4-phenylbenzoyl)amino]-3H-quinolin-4-yl]phenoxy]methyl]triazol-1-yl]ethyl]triazol-4-yl]methylamino]-2-oxoethyl]amino]phenyl]-5-amino-N-tert-butyl-2-methylsulfanylthieno[2,3-d]pyrimidine-6-carboxamide	553581: Agonist activity at human LH receptor expressed in CHO-K1 cells assessed as stimulation of luciferase activity by CRE-driven luciferase reporter gene assay	ec50	0.0240	uM
4-[3-[[2-[[1-[2-[2-[4-[[4-[(4R)-1-acetyl-2,2,4-trimethyl-6-[(4-phenylbenzoyl)amino]-3H-quinolin-4-yl]phenoxy]methyl]triazol-1-yl]ethoxy]ethyl]triazol-4-yl]methylamino]-2-oxoethyl]amino]phenyl]-5-amino-N-tert-butyl-2-methylsulfanylthieno[2,3-d]pyrimidine-6-carboxamide	553581: Agonist activity at human LH receptor expressed in CHO-K1 cells assessed as stimulation of luciferase activity by CRE-driven luciferase reporter gene assay	ec50	0.0270	uM
4-[3-[[2-[[1-[2-[2-[2-[2-[2-[4-[[4-[(4S)-1-acetyl-2,2,4-trimethyl-6-[(4-phenylbenzoyl)amino]-3H-quinolin-4-yl]phenoxy]methyl]triazol-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]triazol-4-yl]methylamino]-2-oxoethyl]amino]phenyl]-5-amino-N-tert-butyl-2-methylsulfanylthieno[2,3-d]pyrimidine-6-carboxamide	553581: Agonist activity at human LH receptor expressed in CHO-K1 cells assessed as stimulation of luciferase activity by CRE-driven luciferase reporter gene assay	ec50	0.0390	uM
4-[3-[[2-[[1-[2-[2-[2-[4-[[4-[(4R)-1-acetyl-2,2,4-trimethyl-6-[(4-phenylbenzoyl)amino]-3H-quinolin-4-yl]phenoxy]methyl]triazol-1-yl]ethoxy]ethoxy]ethyl]triazol-4-yl]methylamino]-2-oxoethyl]amino]phenyl]-5-amino-N-tert-butyl-2-methylsulfanylthieno[2,3-d]pyrimidine-6-carboxamide	553581: Agonist activity at human LH receptor expressed in CHO-K1 cells assessed as stimulation of luciferase activity by CRE-driven luciferase reporter gene assay	ec50	0.0430	uM
4-[3-[[2-[[1-[2-[2-[2-[2-[2-[4-[[4-[(4R)-1-acetyl-2,2,4-trimethyl-6-[(4-phenylbenzoyl)amino]-3H-quinolin-4-yl]phenoxy]methyl]triazol-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]triazol-4-yl]methylamino]-2-oxoethyl]amino]phenyl]-5-amino-N-tert-butyl-2-methylsulfanylthieno[2,3-d]pyrimidine-6-carboxamide	553581: Agonist activity at human LH receptor expressed in CHO-K1 cells assessed as stimulation of luciferase activity by CRE-driven luciferase reporter gene assay	ec50	0.0550	uM
4-[3-[[2-[[1-[2-[2-[2-[2-[4-[[4-[(4S)-1-acetyl-2,2,4-trimethyl-6-[(4-phenylbenzoyl)amino]-3H-quinolin-4-yl]phenoxy]methyl]triazol-1-yl]ethoxy]ethoxy]ethoxy]ethyl]triazol-4-yl]methylamino]-2-oxoethyl]amino]phenyl]-5-amino-N-tert-butyl-2-methylsulfanylthieno[2,3-d]pyrimidine-6-carboxamide	553581: Agonist activity at human LH receptor expressed in CHO-K1 cells assessed as stimulation of luciferase activity by CRE-driven luciferase reporter gene assay	ec50	0.0570	uM
4-[3-[[2-[[1-[2-[2-[2-[2-[4-[[4-[(4R)-1-acetyl-2,2,4-trimethyl-6-[(4-phenylbenzoyl)amino]-3H-quinolin-4-yl]phenoxy]methyl]triazol-1-yl]ethoxy]ethoxy]ethoxy]ethyl]triazol-4-yl]methylamino]-2-oxoethyl]amino]phenyl]-5-amino-N-tert-butyl-2-methylsulfanylthieno[2,3-d]pyrimidine-6-carboxamide	553581: Agonist activity at human LH receptor expressed in CHO-K1 cells assessed as stimulation of luciferase activity by CRE-driven luciferase reporter gene assay	ec50	0.0610	uM
4-[3-[[2-[[1-[2-[2-[2-[4-[[4-[(4S)-1-acetyl-2,2,4-trimethyl-6-[(4-phenylbenzoyl)amino]-3H-quinolin-4-yl]phenoxy]methyl]triazol-1-yl]ethoxy]ethoxy]ethyl]triazol-4-yl]methylamino]-2-oxoethyl]amino]phenyl]-5-amino-N-tert-butyl-2-methylsulfanylthieno[2,3-d]pyrimidine-6-carboxamide	553581: Agonist activity at human LH receptor expressed in CHO-K1 cells assessed as stimulation of luciferase activity by CRE-driven luciferase reporter gene assay	ec50	0.0750	uM
5-[1-(4-tert-butylphenyl)-3-pyridin-3-ylpyrazol-5-yl]-N-[2-(4-hydroxyphenyl)ethyl]pentanamide	306713: Agonist activity at human LH receptor expressed in CHO cells assessed as production of cAMP after 60 mins by SPA	ec50	0.0800	uM
4-[3-[[2-[[1-[2-[2-[4-[[4-[(4S)-1-acetyl-2,2,4-trimethyl-6-[(4-phenylbenzoyl)amino]-3H-quinolin-4-yl]phenoxy]methyl]triazol-1-yl]ethoxy]ethyl]triazol-4-yl]methylamino]-2-oxoethyl]amino]phenyl]-5-amino-N-tert-butyl-2-methylsulfanylthieno[2,3-d]pyrimidine-6-carboxamide	553581: Agonist activity at human LH receptor expressed in CHO-K1 cells assessed as stimulation of luciferase activity by CRE-driven luciferase reporter gene assay	ec50	0.0800	uM
4-(4-chlorophenyl)-N-[4-fluoro-3-(trifluoromethoxy)phenyl]-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxamide	1527182: Antagonist activity at human luteinizing hormone receptor assessed as reduction in agonist-induced cAMP production preincubated for 20 mins followed by agonist solution addition after 60 mins by cell based TR-FRET assay	ic50	0.0810	uM
4-(4-chlorophenyl)-N-phenyl-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxamide	1527182: Antagonist activity at human luteinizing hormone receptor assessed as reduction in agonist-induced cAMP production preincubated for 20 mins followed by agonist solution addition after 60 mins by cell based TR-FRET assay	ic50	0.0950	uM
(5S)-5-(4-chlorophenyl)-N-[4-(4-fluorophenoxy)phenyl]-7,8-dihydro-5H-1,6-naphthyridine-6-carboxamide	1527182: Antagonist activity at human luteinizing hormone receptor assessed as reduction in agonist-induced cAMP production preincubated for 20 mins followed by agonist solution addition after 60 mins by cell based TR-FRET assay	ic50	0.0960	uM
(5S)-N-[4-(4-fluorophenoxy)phenyl]-5-(4-fluorophenyl)-7,8-dihydro-5H-1,6-naphthyridine-6-carboxamide	1527182: Antagonist activity at human luteinizing hormone receptor assessed as reduction in agonist-induced cAMP production preincubated for 20 mins followed by agonist solution addition after 60 mins by cell based TR-FRET assay	ic50	0.1020	uM
N-(4-chlorophenyl)-4-(4-methoxyphenyl)-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxamide	1527182: Antagonist activity at human luteinizing hormone receptor assessed as reduction in agonist-induced cAMP production preincubated for 20 mins followed by agonist solution addition after 60 mins by cell based TR-FRET assay	ic50	0.1070	uM
4-(4-chlorophenyl)-N-[4-(4-fluorophenoxy)phenyl]-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxamide	1527182: Antagonist activity at human luteinizing hormone receptor assessed as reduction in agonist-induced cAMP production preincubated for 20 mins followed by agonist solution addition after 60 mins by cell based TR-FRET assay	ic50	0.1270	uM
N-[(2S)-1-amino-3-(3-hydroxyphenyl)-1-oxopropan-2-yl]-6-[[1-(4-tert-butylphenyl)-3-pyridin-2-ylpyrazol-5-yl]amino]hexanamide	306713: Agonist activity at human LH receptor expressed in CHO cells assessed as production of cAMP after 60 mins by SPA	ec50	0.1500	uM
N-[(1S)-2-amino-1-(4-hydroxyphenyl)-2-oxoethyl]-6-[[1-(4-tert-butylphenyl)-3-pyridin-2-ylpyrazol-5-yl]amino]hexanamide	306713: Agonist activity at human LH receptor expressed in CHO cells assessed as production of cAMP after 60 mins by SPA	ec50	0.1700	uM
N-(3-chloro-4-fluorophenyl)-4-(4-chlorophenyl)-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxamide	1527182: Antagonist activity at human luteinizing hormone receptor assessed as reduction in agonist-induced cAMP production preincubated for 20 mins followed by agonist solution addition after 60 mins by cell based TR-FRET assay	ic50	0.1740	uM
(5S)-N-[2-(4-fluorophenoxy)pyrimidin-5-yl]-5-(4-fluorophenyl)-7,8-dihydro-5H-1,6-naphthyridine-6-carboxamide	1527182: Antagonist activity at human luteinizing hormone receptor assessed as reduction in agonist-induced cAMP production preincubated for 20 mins followed by agonist solution addition after 60 mins by cell based TR-FRET assay	ic50	0.1850	uM
N-[(2S)-4-amino-4-oxo-1-phenylbutan-2-yl]-5-[1-(4-tert-butylphenyl)-3-pyridin-4-ylpyrazol-5-yl]pentanamide	306713: Agonist activity at human LH receptor expressed in CHO cells assessed as production of cAMP after 60 mins by SPA	ec50	0.1900	uM
(4S)-N-(3,5-dimethoxyphenyl)-4-phenyl-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxamide	1527182: Antagonist activity at human luteinizing hormone receptor assessed as reduction in agonist-induced cAMP production preincubated for 20 mins followed by agonist solution addition after 60 mins by cell based TR-FRET assay	ic50	0.1930	uM
N-(3,5-dimethoxyphenyl)-4-(4-methoxyphenyl)-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxamide	1527182: Antagonist activity at human luteinizing hormone receptor assessed as reduction in agonist-induced cAMP production preincubated for 20 mins followed by agonist solution addition after 60 mins by cell based TR-FRET assay	ic50	0.2070	uM
5-amino-N-tert-butyl-4-(3-methoxyphenyl)-2-methylsulfanylthieno[2,3-d]pyrimidine-6-carboxamide	1118936: Agonist activity at LHCGR (unknown origin)	ec50	0.2200	uM
N-[(2S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]-5-[1-(4-tert-butylphenyl)-3-pyridin-4-ylpyrazol-5-yl]pentanamide	306713: Agonist activity at human LH receptor expressed in CHO cells assessed as production of cAMP after 60 mins by SPA	ec50	0.2500	uM
N-(3-chlorophenyl)-4-(4-methoxyphenyl)-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxamide	1527182: Antagonist activity at human luteinizing hormone receptor assessed as reduction in agonist-induced cAMP production preincubated for 20 mins followed by agonist solution addition after 60 mins by cell based TR-FRET assay	ic50	0.2750	uM
(5S)-N-[6-(4-fluorophenoxy)-3-pyridinyl]-5-(4-fluorophenyl)-7,8-dihydro-5H-1,6-naphthyridine-6-carboxamide	1527182: Antagonist activity at human luteinizing hormone receptor assessed as reduction in agonist-induced cAMP production preincubated for 20 mins followed by agonist solution addition after 60 mins by cell based TR-FRET assay	ic50	0.3120	uM
4-(4-chlorophenyl)-N-(3-phenoxyphenyl)-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxamide	1527182: Antagonist activity at human luteinizing hormone receptor assessed as reduction in agonist-induced cAMP production preincubated for 20 mins followed by agonist solution addition after 60 mins by cell based TR-FRET assay	ic50	0.3320	uM
N-(3,5-dichlorophenyl)-4-(4-methoxyphenyl)-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxamide	1527182: Antagonist activity at human luteinizing hormone receptor assessed as reduction in agonist-induced cAMP production preincubated for 20 mins followed by agonist solution addition after 60 mins by cell based TR-FRET assay	ic50	0.3780	uM
(4S)-N-(3,5-dichlorophenyl)-4-(4-methoxyphenyl)-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxamide	1527182: Antagonist activity at human luteinizing hormone receptor assessed as reduction in agonist-induced cAMP production preincubated for 20 mins followed by agonist solution addition after 60 mins by cell based TR-FRET assay	ic50	0.4030	uM
2-[3-[(2,6-dimethylphenoxy)methyl]-4-methoxyphenyl]-3-(furan-2-ylmethyl)-1,2-dihydroquinazolin-4-one	2130682: Agonist activity at LHCGR (unknown origin)	ec50	0.4800	uM
4-(4-chlorophenyl)-N-(3,5-dichlorophenyl)-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxamide	1527182: Antagonist activity at human luteinizing hormone receptor assessed as reduction in agonist-induced cAMP production preincubated for 20 mins followed by agonist solution addition after 60 mins by cell based TR-FRET assay	ic50	0.4860	uM
N-[(2S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]-3-[1-(4-tert-butylphenyl)-3-isoquinolin-3-ylpyrazol-5-yl]benzamide	306713: Agonist activity at human LH receptor expressed in CHO cells assessed as production of cAMP after 60 mins by SPA	ec50	0.5000	uM
N-(3,5-dimethylphenyl)-4-(4-methoxyphenyl)-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxamide	1527182: Antagonist activity at human luteinizing hormone receptor assessed as reduction in agonist-induced cAMP production preincubated for 20 mins followed by agonist solution addition after 60 mins by cell based TR-FRET assay	ic50	0.5800	uM
5-amino-N-tert-butyl-4-(2,3-dimethoxyphenyl)-2-methylsulfanylthieno[2,3-d]pyrimidine-6-carboxamide	266949: Agonist activity at LHCGR expressed in HEK293 EM cells measured by intracellular cAMP accumulation	ec50	0.8000	uM
5-amino-N-tert-butyl-4-(3-methoxyphenyl)-N-methyl-2-methylsulfanylthieno[2,3-d]pyrimidine-6-carboxamide	266949: Agonist activity at LHCGR expressed in HEK293 EM cells measured by intracellular cAMP accumulation	ec50	0.8000	uM
tert-butyl 5-amino-4-(3-methoxyphenyl)-2-methylsulfanylthieno[2,3-d]pyrimidine-6-carboxylate	266949: Agonist activity at LHCGR expressed in HEK293 EM cells measured by intracellular cAMP accumulation	ec50	1.1000	uM
5-amino-N-tert-butyl-4-(3-fluorophenyl)-2-methylsulfanylthieno[2,3-d]pyrimidine-6-carboxamide	266949: Agonist activity at LHCGR expressed in HEK293 EM cells measured by intracellular cAMP accumulation	ec50	1.2000	uM
5-amino-N-tert-butyl-4-(2-fluoro-3-methoxyphenyl)-2-methylsulfanylthieno[2,3-d]pyrimidine-6-carboxamide	266949: Agonist activity at LHCGR expressed in HEK293 EM cells measured by intracellular cAMP accumulation	ec50	1.5000	uM
(3,5-diphenylphenyl) N-cyclopentylcarbamate	414569: Agonist activity at human luteinizing hormone receptor expressed in CHOK1 cells assessed as c-AMP-mediated luciferase production	ec50	1.6000	uM
N-(3,5-dichlorophenyl)-4-phenyl-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxamide	1527182: Antagonist activity at human luteinizing hormone receptor assessed as reduction in agonist-induced cAMP production preincubated for 20 mins followed by agonist solution addition after 60 mins by cell based TR-FRET assay	ic50	1.6200	uM
N-(3-carbamoyl-4-fluorophenyl)-4-(4-methoxyphenyl)-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxamide	1527182: Antagonist activity at human luteinizing hormone receptor assessed as reduction in agonist-induced cAMP production preincubated for 20 mins followed by agonist solution addition after 60 mins by cell based TR-FRET assay	ic50	1.6800	uM
N-(3,5-dichlorophenyl)-4-(3,4-difluorophenyl)-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxamide	1527182: Antagonist activity at human luteinizing hormone receptor assessed as reduction in agonist-induced cAMP production preincubated for 20 mins followed by agonist solution addition after 60 mins by cell based TR-FRET assay	ic50	1.8500	uM
5-amino-N-tert-butyl-4-(3-hydroxyphenyl)-2-methylsulfanylthieno[2,3-d]pyrimidine-6-carboxamide	266949: Agonist activity at LHCGR expressed in HEK293 EM cells measured by intracellular cAMP accumulation	ec50	1.9000	uM
N-[(2S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]-5-[1-(4-tert-butylphenyl)-5-pyridin-4-ylpyrazol-3-yl]pentanamide	306713: Agonist activity at human LH receptor expressed in CHO cells assessed as production of cAMP after 60 mins by SPA	ec50	2.3000	uM
N-(3,5-dichlorophenyl)-4-(6-oxo-1H-pyridin-3-yl)-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxamide	1527182: Antagonist activity at human luteinizing hormone receptor assessed as reduction in agonist-induced cAMP production preincubated for 20 mins followed by agonist solution addition after 60 mins by cell based TR-FRET assay	ic50	2.3100	uM

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Org 41841	affects binding, increases activity	3
Benzo(a)pyrene	increases methylation, increases mutagenesis	2
8-Bromo Cyclic Adenosine Monophosphate	increases expression, decreases reaction, decreases expression	2
bisphenol A	increases expression, affects cotreatment, decreases reaction	1
alpha-naphthoflavone	decreases reaction, increases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
cyanoginosin LR	decreases expression	1
CGP 52608	affects binding, increases reaction	1
5-amino-2-methylsulfanyl-4-(3-(2-morpholin-4-ylacetylamino)phenyl)thieno(2,3-d)pyrimidine-6-carboxylic acid tert-butylamide	affects binding	1
fatostatin	affects binding, decreases reaction, increases reaction, decreases expression	1
Cyclic AMP	increases abundance, increases activity, increases reaction, decreases reaction	1
Amiodarone	increases expression	1
Atrazine	decreases reaction, increases expression	1
Vehicle Emissions	decreases methylation	1
Estradiol	decreases reaction, increases abundance, increases activity	1
Chorionic Gonadotropin	affects cotreatment, decreases reaction, increases expression	1
Gonadotropins, Equine	affects cotreatment, decreases reaction, increases expression	1
Melitten	affects binding, increases response to substance	1
T-2 Toxin	decreases reaction, increases expression	1
Testosterone	affects cotreatment, increases expression	1
Tetrachlorodibenzodioxin	decreases reaction, increases expression	1
1-Methyl-3-isobutylxanthine	decreases reaction, increases expression	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	increases expression	1
Particulate Matter	decreases expression	1

ChEMBL screening assays

54 unique, capped per target: 35 binding, 18 functional, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1018018	Binding	Displacement of [3H]Org43553 from human luteinizing hormone receptor expressed in CHOK1 cells at 10 uM by scintillation spectrometry	Substituted terphenyl compounds as the first class of low molecular weight allosteric inhibitors of the luteinizing hormone receptor. — J Med Chem
CHEMBL1018023	Functional	Antagonist activity at human luteinizing hormone receptor expressed in CHOK1 cells assessed as decrease in recombinant luteinizing hormone activation potency at 10 uM by c-AMP-mediated luciferase assay	Substituted terphenyl compounds as the first class of low molecular weight allosteric inhibitors of the luteinizing hormone receptor. — J Med Chem
CHEMBL4323786	ADMET	Agonist activity at human luteinizing hormone receptor incubated for 60 mins by cell based TR-FRET assay	Discovery of BAY-298 and BAY-899: Tetrahydro-1,6-naphthyridine-Based, Potent, and Selective Antagonists of the Luteinizing Hormone Receptor Which Reduce Sex Hormone Levels in Vivo. — J Med Chem

Cellosaurus cell lines

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

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

Cellosaurus	Name	Category	Sex
CVCL_C0T2	ACTOne LHCGR	Transformed cell line	Female
CVCL_KV43	cAMP Hunter CHO-K1 LHCGR Gs	Spontaneously immortalized cell line	Female
CVCL_KX90	PathHunter CHO-K1 LHCGR beta-arrestin	Spontaneously immortalized cell line	Female
CVCL_YK16	HEK293 LHCGR Fluo-HiTSeeker	Transformed cell line	Female
CVCL_YK17	HEK293 LHCGR HiTSeeker	Transformed cell line	Female
CVCL_YK52	U2OS LHCGR cAMP-Nomad	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03718234	PHASE1	COMPLETED	Subcutaneous Hydrocortisone Children With Congenital Adrenal Hyperplasia
NCT00250159	Not specified	RECRUITING	Natural History Study of Patients With Excess Androgen
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
NCT05058781	Not specified	RECRUITING	Minipuberty in Infants Born With Potential Hypogonadism Hypogonadotrope
NCT06692049	Not specified	RECRUITING	Gonadal Tissue Cryopreservation for Fertility Preservation in Children with a Disorder of Sex Development
NCT06989593	Not specified	RECRUITING	Breaking Silence Through Story: A Narrative Medicine Intervention for Parents of Children With Urogenital Conditions
NCT06723938	Not specified	RECRUITING	Phenotypic and Genotypic Characterisation of a Large, Multicentre Italian Cohort of 46, XY DSD Patients
NCT00172510	Not specified	UNKNOWN	Mutation Analysis of 17α-Hydroxylase
NCT00173654	Not specified	UNKNOWN	Mutation Analysis of 17βhydroxysteroid Dehydrogenase 3 Deficiency