LGR5

Summary

LGR5 (leucine rich repeat containing G protein-coupled receptor 5, HGNC:4504) is a protein-coding gene on chromosome 12q21.1, encoding Leucine-rich repeat-containing G-protein coupled receptor 5 (O75473). Receptor for R-spondins that potentiates the canonical Wnt signaling pathway and acts as a stem cell marker of the intestinal epithelium and the hair follicle.

The protein encoded by this gene is a leucine-rich repeat-containing receptor (LGR) and member of the G protein-coupled, 7-transmembrane receptor (GPCR) superfamily. The encoded protein is a receptor for R-spondins and is involved in the canonical Wnt signaling pathway. This protein plays a role in the formation and maintenance of adult intestinal stem cells during postembryonic development. Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 8549 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 151 total
• Druggable target: yes
• MANE Select transcript: NM_003667

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4504
Approved symbol	LGR5
Name	leucine rich repeat containing G protein-coupled receptor 5
Location	12q21.1
Locus type	gene with protein product
Status	Approved
Aliases	HG38, FEX
Ensembl gene	ENSG00000139292
Ensembl biotype	protein_coding
OMIM	606667
Entrez	8549

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding, 3 retained_intron

ENST00000266674, ENST00000536515, ENST00000540815, ENST00000547310, ENST00000549015, ENST00000550851, ENST00000856956, ENST00000856957

RefSeq mRNA: 3 — MANE Select: NM_003667 NM_001277226, NM_001277227, NM_003667

CCDS: CCDS61194, CCDS61195, CCDS9000

Canonical transcript exons

ENST00000266674 — 18 exons

Exon	Start	End
ENSE00000937407	71566841	71566912
ENSE00001669202	71439798	71440292
ENSE00002419429	71583647	71586310
ENSE00003459670	71556619	71556690
ENSE00003462169	71566632	71566700
ENSE00003482262	71561781	71561852
ENSE00003498271	71582456	71582539
ENSE00003501210	71524406	71524477
ENSE00003531367	71553073	71553288
ENSE00003550633	71535115	71535186
ENSE00003560993	71566404	71566475
ENSE00003561942	71559586	71559654
ENSE00003588399	71504614	71504685
ENSE00003588922	71578804	71578929
ENSE00003649237	71571514	71571579
ENSE00003660050	71577925	71577996
ENSE00003661069	71580278	71580423
ENSE00003661545	71572850	71572921

Expression profiles

Bgee: expression breadth ubiquitous, 217 present calls, max score 94.46.

FANTOM5 (CAGE): breadth broad, TPM avg 5.8371 / max 618.8187, expressed in 487 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
126809	5.7046	480
126810	0.1325	61

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
hair follicle	UBERON:0002073	94.46	gold quality
gastrocnemius	UBERON:0001388	87.45	gold quality
placenta	UBERON:0001987	87.42	gold quality
diaphragm	UBERON:0001103	87.26	gold quality
skin of hip	UBERON:0001554	87.10	gold quality
dorsal root ganglion	UBERON:0000044	86.47	gold quality
muscle of leg	UBERON:0001383	86.42	gold quality
vastus lateralis	UBERON:0001379	86.20	gold quality
biceps brachii	UBERON:0001507	86.15	gold quality
hindlimb stylopod muscle	UBERON:0004252	86.00	gold quality
skeletal muscle organ	UBERON:0014892	85.95	gold quality
muscle organ	UBERON:0001630	85.94	gold quality
right uterine tube	UBERON:0001302	85.77	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	85.45	gold quality
corpus callosum	UBERON:0002336	85.37	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	85.12	gold quality
skeletal muscle tissue	UBERON:0001134	85.01	gold quality
quadriceps femoris	UBERON:0001377	84.05	gold quality
gluteal muscle	UBERON:0002000	83.52	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	82.89	gold quality
deltoid	UBERON:0001476	82.72	gold quality
spinal cord	UBERON:0002240	81.24	gold quality
muscle tissue	UBERON:0002385	79.89	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.94	gold quality
endometrium	UBERON:0001295	78.80	gold quality
upper arm skin	UBERON:0004263	77.11	gold quality
trigeminal ganglion	UBERON:0001675	76.69	gold quality
triceps brachii	UBERON:0001509	76.52	gold quality
rectum	UBERON:0001052	75.49	gold quality
fallopian tube	UBERON:0003889	74.18	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-10662	yes	177059.22
E-MTAB-7008	yes	71.65
E-GEOD-125970	yes	16.97
E-ANND-3	yes	8.40

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NEUROG1, OLIG2, TCF4, TFAP4

miRNA regulators (miRDB)

71 targeting LGR5, 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-190A-3P	100.00	80.35	5520
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-8076	99.78	68.52	1170
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-802	99.61	67.70	1254
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-582-5P	99.47	70.79	2635

Literature-anchored findings (GeneRIF, showing 40)

• Gpr49 may be critically involved in the development of hepatocellular carcinoma with beta-catenin mutations (PMID:12601349)
• GPR49 may have a role in human colon and ovarian primary tum (PMID:16575208)
• LGR5 is a Wnt target gene in a human colon cancer cell line (PMID:17934449)
• GPR49 is expressed downstream of Hedgehog signaling and promotes cell proliferation and tumor formation in cases of basal cell carcinoma. (PMID:18688030)
• Lgr5 is a potential marker of intestinal stem cells in humans (PMID:19030762)
• Lgr5 has been recently identified as a novel stem cell marker of the intestinal epithelium and the hair follicle[REVIEW] (PMID:19197002)
• Lgr5 expression detected in 70% of BE cases and between 90 and 100% of advanced dysplastic lesions and EAC. Lgr5 has potential utility as biomarker for BE-associated dysplasia and EAC. (PMID:19549212)
• LGR5, a stem cell marker, showed an increase in F3-Ngn1, although transient overexpression of Ngn1 did not induce upregulation of LGR5, suggesting that LGR5 is not a direct transcriptional target of Ngn1. (PMID:19813087)
• gene [coding region] mutations excluded as being involved in the pathogenesis of autosomal-dominant ankyloglossia (PMID:20042737)
• The results suggest that up-regulation of Lgr5 expression, especially in female patients, may play an important role in colorectal carcinogenesis, probably through the WNT/beta-catenin pathway, but not involve the progression of the colorectal carcinomas. (PMID:20195621)
• Involvement and overexpression of LGR5, not only in early events but also in late events in colorectal tumorigenesis. (PMID:20384634)
• High level of LGR5 expression was associated with colorectal cancer. (PMID:21125339)
• High LGR5 is associated with colorectal tumorigenesis. (PMID:21273608)
• The stem cell marker LgR5 is expressed in esophageal adenocarcinomas, irrespective of association with Barrett’s esophagus, and appears to have negative impact on survival. (PMID:21345220)
• The study suggests a connection between CD133 and EGR1 and emphasises the importance of the EGR1/TCF4/CD133/LGR5 network in colorectal cancer. (PMID:21436631)
• Results point to rare evidence of Lgr5 positive stem cell like cells in the metastatic cascade of colorectal cancer. (PMID:21577318)
• LGR4 and LGR5 bind the R-spondins with high affinity and mediate the potentiation of Wnt/beta-catenin signaling by enhancing Wnt-induced LRP6 phosphorylation. (PMID:21693646)
• Loss of LGR5 is associated with colorectal cancer. (PMID:21829496)
• An attenuated mRNA level of the newly identified transcript variant GPR49Delta5 is a negative prognostic marker for disease-associated and recurrence-free survival in STS patients. (PMID:21978106)
• LGR5 expression can be related to cellular stemness and can be considered as a new phenotypic marker of residual human corneal limbal stem cells. (PMID:22322201)
• LGR5 is a part of the Wnt signaling complex at the membrane level to enhance Wnt/beta-catenin signaling. However, internalization of LGR5 does not appear to be essential for potentiating the canonical Wnt signaling pathway. (PMID:22473993)
• LGR5 is differentially expressed in gastrointestinal cancers and that the spatial histoanatomical distribution of LGR5(+) cells has to be considered when their tumour biological significance is sought. (PMID:22530031)
• High AGR2/LGR5 was associated with poor progression-free survival by multivariate analysis. (PMID:22605983)
• The results of this study found suggest that LGR5 plays a role in maintenance and/or survival of brain cancer stem-like cells. (PMID:22805276)
• R-Spondin potentiates Wnt/beta-catenin signaling through orphan receptors LGR4 and LGR5 (PMID:22815884)
• LGR5 and CD44 expression may be coordinately associated with tumor relapse in locally advanced rectal cancer after preoperative chemoradiotherapy (CRT). (PMID:22923071)
• In gastric cancer patients with an active H. pylori infection, Lgr5-positive epithelial cells may be more susceptible to DNA damage than Lgr5-negative cells. (PMID:22945475)
• Lgr5 expression is dependent on the Wnt pathway and overexpression induces clonogenic growth. (PMID:22969042)
• Results suggest that LGR5 expression may be implicated in resistance to chemoradiotherapy (CRT), therefore contributing to tumor relapse in patients with locally advanced rectal cancer treated with preoperative CRT. (PMID:22986809)
• Lgr5 expression remained restricted to cell clusters within developing nephrons in the cortex until postnatal day 7, when expression was permanently silenced. (PMID:22999937)
• Both LGR5(+) and LGR5(-) cells were detected in the tumor tissues of colon cancer patients. (PMID:23081779)
• Expression of Nanog and LGR5 in normal ovaries and in borderline tumors may assist in the early detection and improved prognosis of ovarian cancer (PMID:23092806)
• Aberrant expression of LGR5 regulates epithelial cell phenotype and survival. (PMID:23127514)
• TROY is up-regulated in human colorectal cancer cell lines and in intestinal tumors in mice. It functions as a negative modulator of the Wnt pathway in LGR5-positive stem cells. (PMID:23142137)
• LGR5 small interfering RNA inhibited the survival-promoting effects of PGE2 in RG/C2. (PMID:23349017)
• Leucine-rich repeat-containing G protein-coupled receptor 5 are overexpressed in gastric cancer. (PMID:23356221)
• Our results indicate that Lgr5 may mark adult taste stem or progenitor cells in the posterior portion of the tongue. (PMID:23377989)
• the islet’s beta cells, expressing LGR5 and Nanog markers are the initiating cells of pancreas cancer and LGR5 is a major biomarker for pancreatic ductal adenocarcinomas (PMID:23438436)
• The constitutive internalization of LGR5 to the TGN suggests the existence of novel biochemical roles for its Wnt pathway related, but ill defined signaling program. (PMID:23439653)
• Leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) as a putative human endometrial stem cell marker. (PMID:23475985)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
mus_musculus	Lgr5	ENSMUSG00000020140
rattus_norvegicus	Lgr5	ENSRNOG00000004221
drosophila_melanogaster	Con	FBGN0005775
drosophila_melanogaster	kek3	FBGN0028370
caenorhabditis_elegans	lron-9	WBGENE00011971
caenorhabditis_elegans		WBGENE00020649

Paralogs (22): CHADL (ENSG00000100399), LGI1 (ENSG00000108231), LGR6 (ENSG00000133067), CHAD (ENSG00000136457), LRIG3 (ENSG00000139263), LRIG1 (ENSG00000144749), LRRTM2 (ENSG00000146006), LRIT1 (ENSG00000148602), LGI2 (ENSG00000153012), LGI4 (ENSG00000153902), LRRC52 (ENSG00000162763), ELFN2 (ENSG00000166897), LGI3 (ENSG00000168481), LRG1 (ENSG00000171236), CPN2 (ENSG00000178772), LRIT3 (ENSG00000183423), LRRC26 (ENSG00000184709), LRIG2 (ENSG00000198799), LGR4 (ENSG00000205213), ELFN1 (ENSG00000225968), LRRC24 (ENSG00000254402), TRIL (ENSG00000255690)

Protein

Protein identifiers

Leucine-rich repeat-containing G-protein coupled receptor 5 — O75473 (reviewed: O75473)

Alternative names: G-protein coupled receptor 49, G-protein coupled receptor 67, G-protein coupled receptor HG38

All UniProt accessions (2): A0A0A8K8C7, O75473

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for R-spondins that potentiates the canonical Wnt signaling pathway and acts as a stem cell marker of the intestinal epithelium and the hair follicle. Upon binding to R-spondins (RSPO1, RSPO2, RSPO3 or RSPO4), associates with phosphorylated LRP6 and frizzled receptors that are activated by extracellular Wnt receptors, triggering the canonical Wnt signaling pathway to increase expression of target genes. In contrast to classical G-protein coupled receptors, does not activate heterotrimeric G-proteins to transduce the signal. Involved in the development and/or maintenance of the adult intestinal stem cells during postembryonic development.

Subunit / interactions. Identified in a complex composed of RNF43, LGR5 and RSPO1. Also interacts with other R-spondin ligands, including RSPO2, RSPO3 and RSPO4.

Subcellular location. Cell membrane. Golgi apparatus. trans-Golgi network membrane.

Tissue specificity. Expressed in skeletal muscle, placenta, spinal cord, and various region of brain. Expressed at the base of crypts in colonic and small mucosa stem cells. In premalignant cancer expression is not restricted to the cript base. Overexpressed in cancers of the ovary, colon and liver.

Miscellaneous. LGR5 is used as a marker of adult tissue stem cells in the intestine, stomach, hair follicle, and mammary epithelium.

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

Isoforms (3)

UniProt ID	Names	Canonical?
O75473-1	1	yes
O75473-2	2
O75473-3	3

RefSeq proteins (3): NP_001264155, NP_001264156, NP_003658* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR000372	LRRNT	Domain
IPR001611	Leu-rich_rpt	Repeat
IPR002131	Gphrmn_rcpt_fam	Family
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR017452	GPCR_Rhodpsn_7TM	Domain
IPR032675	LRR_dom_sf	Homologous_superfamily

Pfam: PF00001, PF00560, PF01462, PF13855

UniProt features (94 total): strand 22, repeat 16, turn 11, topological domain 8, transmembrane region 7, helix 6, glycosylation site 5, disulfide bond 5, mutagenesis site 5, splice variant 2, sequence variant 2, sequence conflict 2, signal peptide 1, chain 1, domain 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
4UFR	X-RAY DIFFRACTION	2.2
4KNG	X-RAY DIFFRACTION	2.5
4BSR	X-RAY DIFFRACTION	3.2
4BSS	X-RAY DIFFRACTION	3.2
4BSU	X-RAY DIFFRACTION	3.2
4BST	X-RAY DIFFRACTION	4.3
4UFS	X-RAY DIFFRACTION	4.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75473-F1	80.34	0.58

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): 34–40, 38–52, 348–373, 479–541, 637–712

Glycosylation sites (5): 63, 77, 208, 500, 792

Mutagenesis-validated functional residues (5):

Position	Phenotype
146	abolishes activation of wnt signaling.
170	abolishes activation of wnt signaling.
190	abolishes activation of wnt signaling.
861	impaired internalization to the trans-golgi network; when associated with a-864.
864	impaired internalization to the trans-golgi network; when associated with a-861.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-4641263	Regulation of FZD by ubiquitination
R-HSA-162582	Signal Transduction
R-HSA-195721	Signaling by WNT
R-HSA-201681	TCF dependent signaling in response to WNT

MSigDB gene sets: 224 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GSE45365_NK_CELL_VS_CD8_TCELL_UP, ATF_B, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, MODULE_52, GOBP_EPITHELIUM_DEVELOPMENT, LEE_NEURAL_CREST_STEM_CELL_DN, BENPORATH_ES_WITH_H3K27ME3, LUCAS_HNF4A_TARGETS_DN, XU_GH1_AUTOCRINE_TARGETS_UP, JAEGER_METASTASIS_DN, GOBP_OOGENESIS, CREBP1_Q2, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, MODULE_16

GO Biological Process (9): hair follicle development (GO:0001942), G protein-coupled receptor signaling pathway (GO:0007186), oocyte differentiation (GO:0009994), regulation of cell population proliferation (GO:0042127), inner ear development (GO:0048839), positive regulation of canonical Wnt signaling pathway (GO:0090263), epithelial cell proliferation involved in renal tubule morphogenesis (GO:2001013), signal transduction (GO:0007165), positive regulation of Wnt signaling pathway (GO:0030177)

GO Molecular Function (4): transmembrane signaling receptor activity (GO:0004888), G protein-coupled receptor activity (GO:0004930), protein-hormone receptor activity (GO:0016500), protein binding (GO:0005515)

GO Cellular Component (4): plasma membrane (GO:0005886), trans-Golgi network membrane (GO:0032588), Golgi apparatus (GO:0005794), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
TCF dependent signaling in response to WNT	1
Signal Transduction	1
Signaling by WNT	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure development	2
regulation of cellular process	2
signaling receptor activity	2
hair cycle process	1
skin epidermis development	1
G protein-coupled receptor activity	1
signal transduction	1
developmental process involved in reproduction	1
cell differentiation	1
oogenesis	1
cell population proliferation	1
ear development	1
positive regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
epithelial cell proliferation	1
renal tubule morphogenesis	1
cell communication	1
cellular process	1
signaling	1
cellular response to stimulus	1
positive regulation of signal transduction	1
Wnt signaling pathway	1
regulation of Wnt signaling pathway	1
transmembrane signaling receptor activity	1
G protein-coupled receptor signaling pathway	1
binding	1
membrane	1
cell periphery	1
trans-Golgi network	1
organelle membrane	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

4998 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LGR5	RSPO1	Q2MKA7	998
LGR5	RNF43	Q68DV7	949
LGR5	ZNRF3	Q9ULT6	941
LGR5	RSPO2	Q6UXX9	918
LGR5	RSPO3	Q9BXY4	878
LGR5	PROM1	O43490	826
LGR5	OLFM4	Q6UX06	802
LGR5	CD44	P16070	791
LGR5	ASCL2	Q99929	781
LGR5	TNFRSF19	Q9NS68	780
LGR5	NOG	Q13253	774
LGR5	AXIN2	Q9Y2T1	759
LGR5	BMI1	P35226	756
LGR5	R4GMX3	R4GMX3	756
LGR5	CTNNB1	P35222	752

IntAct

16 interactions, top by confidence:

A	B	Type	Score
LGR5	RSPO1	psi-mi:“MI:0915”(physical association)	0.740
LGR5	RSPO1	psi-mi:“MI:0407”(direct interaction)	0.740
LGR5	Rspo2	psi-mi:“MI:0915”(physical association)	0.400
LGR5	Rspo3	psi-mi:“MI:0915”(physical association)	0.400
LGR5	RSPO4	psi-mi:“MI:0915”(physical association)	0.400
Znrf3	LGR5	psi-mi:“MI:0915”(physical association)	0.400
LGR4	FZD7	psi-mi:“MI:0914”(association)	0.350
LGR5	FZD6	psi-mi:“MI:0914”(association)	0.350
APP	RTL1	psi-mi:“MI:0914”(association)	0.350
	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
LGR5	DHPS	psi-mi:“MI:0914”(association)	0.350
INSR	BLTP3B	psi-mi:“MI:0914”(association)	0.350

BioGRID (22): LGR5 (Affinity Capture-MS), ZNRF3 (Co-crystal Structure), Rspo2 (Co-crystal Structure), LGR5 (Affinity Capture-Western), RSPO2 (Reconstituted Complex), LGR5 (Synthetic Lethality), LGR5 (Affinity Capture-Western), DHPS (Affinity Capture-MS), CNPY3 (Affinity Capture-MS), NBR1 (Affinity Capture-MS), LEMD2 (Affinity Capture-MS), LGR5 (Affinity Capture-MS), LGR5 (Affinity Capture-MS), LGR5 (Affinity Capture-MS), LGR5 (Positive Genetic)

ESM2 similar proteins: A1A4H9, A2ARI4, A4IIW9, B0BLW3, B1H234, D3ZAL8, D3ZTV3, D4A6D8, D4A7P2, D4AC13, E5DHB5, E7FE13, F1MLX5, F1MT22, F1NUK7, F7D3V9, O43155, O43300, O75473, P0DM44, P21463, P47750, P56495, Q27987, Q3UVD5, Q5R6B1, Q5R6T0, Q5RDJ4, Q66HV9, Q6RKD8, Q80ZD7, Q80ZD8, Q86UE6, Q86VH5, Q86WK6, Q8BGA3, Q8BGT1, Q8BLU0, Q8BZ81, Q8K377

Diamond homologs: A2ARI4, A8WHP9, B0BLW3, D4AC13, E5DHB5, E7FE13, F1MLX5, F1MT22, F7D3V9, O02833, O75473, P0DM44, P70193, Q3UVD5, Q5NVQ6, Q8BGX3, Q8N967, Q96JA1, Q9BXB1, Q9HBX8, Q9Z1P4, Q9Z2H4, A3KNN3, A4IFA6, A4IIW9, A6H789, A6H793, A6NJW4, E9Q7T7, G3XA59, G5EFX6, O14498, O75093, O75094, O88186, O88279, O88280, O94813, P0C6S8, P14770

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
RSPO2	up-regulates	LGR5	binding
RSPO3	up-regulates	LGR5	binding

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	114
Likely benign	12
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

3109 predictions. Top by Δscore:

Variant	Effect	Δscore
12:71440293:G:GG	donor_gain	1.0000
12:71504612:A:AG	acceptor_gain	1.0000
12:71504613:G:GG	acceptor_gain	1.0000
12:71504613:GA:G	acceptor_gain	1.0000
12:71504681:GAGTT:G	donor_gain	1.0000
12:71504683:GTT:G	donor_gain	1.0000
12:71504684:TT:T	donor_gain	1.0000
12:71504685:TG:T	donor_loss	1.0000
12:71504686:G:C	donor_loss	1.0000
12:71504686:G:GG	donor_gain	1.0000
12:71504687:TAAG:T	donor_loss	1.0000
12:71504688:AA:A	donor_loss	1.0000
12:71504689:AGTAT:A	donor_loss	1.0000
12:71524473:GTTCT:G	donor_gain	1.0000
12:71524478:G:GG	donor_gain	1.0000
12:71535106:A:AG	acceptor_gain	1.0000
12:71535113:A:AG	acceptor_gain	1.0000
12:71535114:G:GG	acceptor_gain	1.0000
12:71535114:GT:G	acceptor_gain	1.0000
12:71535114:GTAT:G	acceptor_gain	1.0000
12:71535187:G:GG	donor_gain	1.0000
12:71553284:GTTCT:G	donor_gain	1.0000
12:71553289:G:GG	donor_gain	1.0000
12:71556691:G:GG	donor_gain	1.0000
12:71566476:G:GG	donor_gain	1.0000
12:71566697:GTCT:G	donor_gain	1.0000
12:71566701:G:GG	donor_gain	1.0000
12:71566923:G:GG	donor_gain	1.0000
12:71571580:G:GG	donor_gain	1.0000
12:71578798:TTGCA:T	acceptor_loss	1.0000

AlphaMissense

5923 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:71553144:T:C	L167P	1.000
12:71553150:T:C	L169P	1.000
12:71440292:T:C	L71P	0.999
12:71504628:A:T	N76I	0.999
12:71504629:C:A	N76K	0.999
12:71504629:C:G	N76K	0.999
12:71524421:C:A	N100K	0.999
12:71524421:C:G	N100K	0.999
12:71524468:T:A	L116H	0.999
12:71524477:T:A	L119H	0.999
12:71524477:T:C	L119P	0.999
12:71535120:T:C	L121P	0.999
12:71535130:T:A	N124K	0.999
12:71535130:T:G	N124K	0.999
12:71535177:T:A	L140H	0.999
12:71535186:T:C	L143P	0.999
12:71553078:T:C	L145P	0.999
12:71553081:A:T	D146V	0.999
12:71553088:C:A	N148K	0.999
12:71553088:C:G	N148K	0.999
12:71553148:G:C	W168C	0.999
12:71553148:G:T	W168C	0.999
12:71553153:A:T	D170V	0.999
12:71553160:T:A	N172K	0.999
12:71553160:T:G	N172K	0.999
12:71553232:C:A	N196K	0.999
12:71553232:C:G	N196K	0.999
12:71553279:T:G	L212W	0.999
12:71553288:T:C	L215P	0.999
12:71556624:T:C	L217P	0.999

dbSNP variants (sampled 300 via entrez): RS1000020616 (12:71467684 A>G), RS1000093177 (12:71464903 T>A), RS1000098011 (12:71509722 T>C), RS1000099668 (12:71507659 C>T), RS1000142622 (12:71547983 C>T), RS1000180728 (12:71474390 T>G), RS1000200685 (12:71440275 C>T), RS1000207683 (12:71558810 T>G), RS1000256232 (12:71541708 C>T), RS1000256784 (12:71502461 G>A), RS1000257732 (12:71563893 A>G), RS1000270825 (12:71521220 A>C), RS1000298449 (12:71480474 A>G), RS1000359732 (12:71551223 C>A,G), RS1000361524 (12:71512905 T>C,G)

Disease associations

OMIM: gene MIM:606667 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST000167_3	Type 2 diabetes	1.000000e-09
GCST000712_11	Type 2 diabetes	4.000000e-06
GCST005047_23	Type 2 diabetes	7.000000e-09
GCST005047_67	Type 2 diabetes	2.000000e-06
GCST005413_9	Type 2 diabetes	2.000000e-06
GCST007993_26	Asthma (adult onset)	7.000000e-07
GCST007995_41	Asthma (childhood onset)	4.000000e-08
GCST009379_339	Type 2 diabetes	2.000000e-14
GCST010118_132	Type 2 diabetes	5.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:1002011	adult onset asthma

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066388 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs17109924	Efficacy	3	fluorouracil	Colonic Neoplasms

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs17109924	LGR5	3	3.25	1	fluorouracil

GtoPdb / IUPHAR curated pharmacology

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

Target class: gpcr — LGR4, LGR5, LGR6

Most potent curated ligand interactions (5 total), top 5:

Ligand	Action	Affinity	Parameter
R-spondin-2	Full agonist	12.0	pEC50
R-spondin-1	Full agonist	11.1	pEC50
R-spondin-3	Full agonist	11.0	pEC50
R-spondin-4	Full agonist	9.4	pEC50
petosemtamab	Binding	9.18	pKd

CTD chemical–gene interactions

49 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases expression	6
Benzo(a)pyrene	decreases expression, increases methylation, affects methylation	4
bisphenol A	affects expression, decreases expression	2
entinostat	decreases expression, affects cotreatment	2
Nickel	decreases expression	2
Quercetin	decreases expression	2
bisphenol F	decreases expression	1
methylmercuric chloride	decreases expression	1
terbufos	increases methylation	1
trichostatin A	decreases expression, increases expression	1
beta-lapachone	decreases expression	1
sodium arsenite	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
Chir 99021	increases expression	1
6-bromoindirubin-3’-oxime	increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	decreases expression	1
4-acetylantroquinonol B	decreases expression	1
NSC 689534	affects binding, decreases expression	1
theaflavin-3,3’-digallate	affects expression	1
Resveratrol	decreases expression	1
Arsenic Trioxide	decreases expression	1
Vorinostat	increases expression	1
Leflunomide	increases expression	1
Arsenic	affects expression	1
Caffeine	increases phosphorylation	1
Copper	affects binding, decreases expression	1
Diethylhexyl Phthalate	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5522536	Binding	Agonist activity at human LGR5 measured upto 100 uM by Discovery X assay	Discovery of Clinical Candidate AZD5462, a Selective Oral Allosteric RXFP1 Agonist for Treatment of Heart Failure. — J Med Chem

Cellosaurus cell lines

7 cell lines: 3 cancer cell line, 2 transformed cell line, 2 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8JQ	Abcam HCT 116 LGR5 KO	Cancer cell line	Male
CVCL_B9LZ	Abcam A-549 LGR5 KO	Cancer cell line	Male
CVCL_D2G6	Abcam MCF-7 LGR5 KO	Cancer cell line	Female
CVCL_D9IK	Ubigene HEK293 LGR5 KO	Transformed cell line	Female
CVCL_E6QY	Genomeditech CHO-K1 H_LGR5	Spontaneously immortalized cell line	Female
CVCL_E6UC	Genomeditech HEK-293 H_LGR5	Transformed cell line	Female
CVCL_KX88	PathHunter CHO-K1 LGR5 beta-arrestin	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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