RSPO2

Summary

RSPO2 (R-spondin 2, HGNC:28583) is a protein-coding gene on chromosome 8q23.1, encoding R-spondin-2 (Q6UXX9). Activator of the canonical Wnt signaling pathway by acting as a ligand for LGR4-6 receptors.

This gene encodes a member of the R-spondin family of proteins. These proteins are secreted ligands of leucine-rich repeat containing G protein-coupled receptors that enhance Wnt signaling through the inhibition of ubiquitin E3 ligases. A chromosomal translocation including this locus that results in the formation of a gene fusion has been identified in multiple human cancers. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 340419 — RefSeq curated summary.

At a glance

• Gene–disease (curated): tetraamelia syndrome 2 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 19
• Clinical variants (ClinVar): 94 total — 4 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 61
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• MANE Select transcript: NM_178565

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28583
Approved symbol	RSPO2
Name	R-spondin 2
Location	8q23.1
Locus type	gene with protein product
Status	Approved
Aliases	MGC35555
Ensembl gene	ENSG00000147655
Ensembl biotype	protein_coding
OMIM	610575
Entrez	340419

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 10 protein_coding, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000276659, ENST00000517781, ENST00000517939, ENST00000520026, ENST00000521502, ENST00000521757, ENST00000521956, ENST00000522333, ENST00000666252, ENST00000851102, ENST00000851103, ENST00000851104, ENST00000971029, ENST00000971030

RefSeq mRNA: 3 — MANE Select: NM_178565 NM_001282863, NM_001317942, NM_178565

CCDS: CCDS6307, CCDS64953, CCDS83314

Canonical transcript exons

ENST00000276659 — 6 exons

Exon	Start	End
ENSE00000981096	107960674	107960817
ENSE00000981098	107958080	107958268
ENSE00001207090	107899316	107901190
ENSE00001378581	108082545	108082807
ENSE00002130230	108083197	108083620
ENSE00003474524	107989056	107989244

Expression profiles

Bgee: expression breadth ubiquitous, 156 present calls, max score 93.38.

FANTOM5 (CAGE): breadth broad, TPM avg 2.6025 / max 255.9542, expressed in 307 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
94389	1.7719	276
94390	0.7419	195
94388	0.0887	33

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	93.38	gold quality
oocyte	CL:0000023	93.30	gold quality
mucosa of stomach	UBERON:0001199	91.57	gold quality
prefrontal cortex	UBERON:0000451	86.14	gold quality
calcaneal tendon	UBERON:0003701	85.52	gold quality
Brodmann (1909) area 9	UBERON:0013540	84.26	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	81.63	gold quality
right lung	UBERON:0002167	81.57	gold quality
frontal cortex	UBERON:0001870	80.89	gold quality
frontal lobe	UBERON:0016525	80.89	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.45	gold quality
right frontal lobe	UBERON:0002810	80.38	gold quality
muscle layer of sigmoid colon	UBERON:0035805	80.05	gold quality
neocortex	UBERON:0001950	79.79	gold quality
anterior cingulate cortex	UBERON:0009835	79.36	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	78.55	gold quality
rectum	UBERON:0001052	78.35	gold quality
primary visual cortex	UBERON:0002436	77.27	gold quality
substantia nigra pars reticulata	UBERON:0001966	76.60	gold quality
cerebral cortex	UBERON:0000956	76.26	gold quality
substantia nigra	UBERON:0002038	76.05	gold quality
occipital lobe	UBERON:0002021	74.29	gold quality
gall bladder	UBERON:0002110	73.04	gold quality
substantia nigra pars compacta	UBERON:0001965	72.67	gold quality
midbrain	UBERON:0001891	72.03	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	71.61	gold quality
postcentral gyrus	UBERON:0002581	71.23	gold quality
upper lobe of left lung	UBERON:0008952	71.09	gold quality
fundus of stomach	UBERON:0001160	71.04	gold quality
superior frontal gyrus	UBERON:0002661	70.63	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-75140	yes	1695.78
E-HCAD-5	yes	907.09
E-MTAB-10485	yes	398.18
E-ANND-3	yes	3.89

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1, FOXQ1

miRNA regulators (miRDB)

68 targeting RSPO2, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-10401-5P	99.99	65.79	948
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-3148	99.97	75.06	6478
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-652-5P	99.91	67.49	505
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-17-3P	99.55	66.77	1311
HSA-MIR-510-3P	99.54	70.06	2965
HSA-MIR-4761-5P	99.51	66.69	804
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-330-3P	99.41	69.95	2521

Literature-anchored findings (GeneRIF, showing 36)

• There is a role for R-spondin2 in keratinocyte proliferation and epidermal thickening in keloid scarring. (PMID:21160497)
• Reduced Rspo-2 levels in osteoarthritis osteoblasts are responsible, at least in part, for their reduced Wnt/beta-catenin signaling and abnormal mineralization. (PMID:22127703)
• using RNA-seq data, identification of multiple fusion transcripts including recurrent gene fusions involving R-spondin family members RSPO2 and RSPO3 that together occur in 10% of colon tumours (PMID:22895193)
• Oocyte-derived R-spondin2 is a paracrine factor essential for primary ovarian follicle development (PMID:23407710)
• data reveal a RSPO2-induced, LGR5-dependent Wnt signaling-negative feedback loop that exerts a net growth-suppressive effect on CRC cells (PMID:24476626)
• results suggest that the expression of RSPO fusion transcripts is related to a subset of colorectal cancers arising in the Japanese population (PMID:24847761)
• These findings suggest that R-Spondin2 may promote hepatic stellate cell activation by enhancing the canonical Wnt pathway. (PMID:24852883)
• Wnt(high) cells were more likely to give rise to Wnt(high) progeny, tended to be more metastatic, and revealed higher levels of RSPO2 expression. (PMID:25769727)
• genetic and functional data indicate that RSPO2 is a susceptibility gene for OPLL (Ossification of the Posterior Longitudinal Ligament of the Spine) (PMID:27374772)
• Rspo2 was found to have a negative regulatory effect during oxidized low density lipoproteininduced macrophage apoptosis by regulating lipid uptake. (PMID:27571704)
• RSPOs facilitate HSC activation and promote liver fibrogenesis by enhancing the Wnt pathway (PMID:27572318)
• Role of RSPO2 in gastric cancer (PMID:28219935)
• RSPO2 suppresses colorectal cancer metastasis by counteracting the Wnt5a/Fzd7-driven noncanonical Wnt pathway. (PMID:28600110)
• Novel targets ANTXR1 and RSPO2 were confirmed to be suppressed by miR-493 directly. (PMID:28651234)
• RSPO2 is a novel target gene of the NOBOX key transcription factor, confirming its important role during the follicular growth in ovary. However, RSPO2 mutations are rare or uncommon in women with primary ovarian insufficiency. (PMID:28743298)
• RSPO2 is upregulated in Idiopathic pulmonary fibrosis. (PMID:29345973)
• results establish that RSPO2, without the LGR4/5/6 receptors, serves as a direct antagonistic ligand to RNF43 and ZNRF3, which together constitute a master switch that governs limb specification; these findings have direct implications for regenerative medicine and WNT-associated cancers (PMID:29769720)
• RSPO2, but not SPON1, specifically promoted the differentiation of midbrain dopaminergic (mDA) neuroblasts into mDA neurons in mouse primary cultures and embryonic stem cells (ESCs). (PMID:30146491)
• Our data show that Wnt pathway inhibition could provide an effective treatment for cancers containing RSPO2 fusion. The RSPO2 fusion will serve as a good biomarker for screening patients to support clinical treatment of digestive system cancers using Wnt pathway inhibitors. (PMID:30250044)
• It promotes osteoblastic differentiation of immature human periodontal ligament cells through the Wnt/beta-catenin signaling pathway. (PMID:30284717)
• High RSPO2 expression is associated with gastric cancer migration and invasion. (PMID:30362605)
• The RSPO2 gene rearrangement leads to oncogenic activation of the Wingless-Type MMTV Integration Site Family signalling pathway in hepatocellular adenomas and hepatocellular carcinoma, represents an alternative mechanism for the development of b-HCA and may drive malignant transformation without additional TERT promoter mutation. (PMID:30901310)
• An EIF3E-RSPO2 fusion was detected in three colorectal serrated polyps (PMID:30916365)
• Study in different human cancer cell lines revealed that Rspo2 is C-mannosylated at Trp150 and Trp153, and these modifications alter its secretory levels and intracellular trafficking. In addition, C-mannosylation of Rspo2 regulated the agonistic activity of Rspo2 in the Wnt/beta-catenin signaling pathway and on cancer cell migration. These results suggested that Cmannosylation of Rspo2 may promote cancer progression. (PMID:30942431)
• A polymorphism within the R-spondin 2 gene predicts outcome in metastatic colorectal cancer patients treated with FOLFIRI/bevacizumab: data from FIRE-3 and TRIBE trials. (PMID:32305727)
• R-spondin2 signaling is required for oocyte-driven intercellular communication and follicular growth. (PMID:32341451)
• R-spondins engage heparan sulfate proteoglycans to potentiate WNT signaling. (PMID:32432544)
• R-spondin2 Suppresses the Progression of Hepatocellular Carcinoma via MAPK Signaling Pathway. (PMID:32581137)
• Role of R-spondin 2 in arterial lymphangiogenesis and atherosclerosis. (PMID:32750106)
• R-Spondins 2 and 3 Are Overexpressed in a Subset of Human Colon and Breast Cancers. (PMID:33320737)
• RSPO2 silence inhibits tumorigenesis of nasopharyngeal carcinoma by ZNRF3/Hedgehog-Gli1 signal pathway. (PMID:34273374)
• RSPO2 inhibits BMP signaling to promote self-renewal in acute myeloid leukemia. (PMID:34407399)
• Evaluation of WNT Signaling Pathway Gene Variants WNT7B rs6519955, SFRP4 rs17171229 and RSPO2 rs611744 in Patients with Dupuytren’s Contracture. (PMID:34573275)
• RSPO2 and RANKL signal through LGR4 to regulate osteoclastic premetastatic niche formation and bone metastasis. (PMID:34847079)
• Identification of a regulatory pathway inhibiting adipogenesis via RSPO2. (PMID:35027768)
• Suppression of Wnt/beta-Catenin Signaling Is Associated with Downregulation of Wnt1, PORCN, and Rspo2 in Alzheimer’s Disease. (PMID:36215026)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	rspo2	ENSDARG00000079570
mus_musculus	Rspo2	ENSMUSG00000051920
rattus_norvegicus	Rspo2	ENSRNOG00000037687

Paralogs (3): RSPO4 (ENSG00000101282), RSPO3 (ENSG00000146374), RSPO1 (ENSG00000169218)

Protein

Protein identifiers

R-spondin-2 — Q6UXX9 (reviewed: Q6UXX9)

Alternative names: Roof plate-specific spondin-2

All UniProt accessions (4): Q6UXX9, A0A590UJ52, E5RGU9, E5RH25

UniProt curated annotations — full annotation on UniProt →

Function. Activator of the canonical Wnt signaling pathway by acting as a ligand for LGR4-6 receptors. Upon binding to LGR4-6 (LGR4, LGR5 or LGR6), LGR4-6 associate 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. Also regulates the canonical Wnt/beta-catenin-dependent pathway and non-canonical Wnt signaling by acting as an inhibitor of ZNRF3, an important regulator of the Wnt signaling pathway. During embryonic development, plays a crucial role in limb specification, amplifying the Wnt signaling pathway independently of LGR4-6 receptors, possibly by acting as a direct antagonistic ligand to RNF43 and ZNRF3, hence governing the number of limbs an embryo should form.

Subunit / interactions. Interacts with WNT1. Binds heparin. Interacts with LGR4, LGR5 and LGR6. Interacts with E3 ubiquitin ligases RNF43 and ZNRF3.

Subcellular location. Secreted.

Disease relevance. Tetraamelia syndrome 2 (TETAMS2) [MIM:618021] A form of tetraamelia, a rare disease characterized by rudimentary appendages or complete absence of all four limbs, and other anomalies such as craniofacial, nervous system, pulmonary, skeletal and urogenital defects. TETAMS2 patients manifest limb deformities, bilateral agenesis of the lungs, abnormalities of the pulmonary vasculature, labioscrotal fold aplasia, and dysmorphic features including bilateral cleft lip/palate, ankyloglossia, mandibular hypoplasia, and microretrognathia. TETAMS2 transmission pattern is consistent with autosomal recessive inheritance. The disease is caused by variants affecting the gene represented in this entry. Humerofemoral hypoplasia with radiotibial ray deficiency (HHRRD) [MIM:618022] A severe disease characterized by reduction of all four limbs as well as hypoplasia of the upper limb girdle and pelvis. Rudimentary finger- or toe-like appendages may be present. HHRRD transmission pattern is consistent with autosomal recessive inheritance. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The FU repeat is required for activation and stabilization of beta-catenin.

Similarity. Belongs to the R-spondin family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q6UXX9-1	1	yes
Q6UXX9-2	2
Q6UXX9-3	3

RefSeq proteins (3): NP_001269792, NP_001304871, NP_848660* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000884	TSP1_rpt	Repeat
IPR006212	Furin_repeat	Repeat
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR036383	TSP1_rpt_sf	Homologous_superfamily
IPR043601	Rspo_Fu-CRD_dom	Domain
IPR051514	R-spondin	Family

Pfam: PF15913

UniProt features (36 total): disulfide bond 11, strand 7, sequence variant 4, splice variant 3, mutagenesis site 2, turn 2, signal peptide 1, chain 1, repeat 1, domain 1, region of interest 1, compositionally biased region 1, glycosylation site 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
8XUM	ELECTRON MICROSCOPY	2.9
8XFS	ELECTRON MICROSCOPY	3.2
8XFP	ELECTRON MICROSCOPY	3.21
8XFT	ELECTRON MICROSCOPY	3.24
9KB8	ELECTRON MICROSCOPY	3.25
8Y69	ELECTRON MICROSCOPY	3.38
9KB9	ELECTRON MICROSCOPY	3.59
9KB7	ELECTRON MICROSCOPY	3.97

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6UXX9-F1	81.09	0.52

Antibody-complex structures (SAbDab): 5 — 8XFP, 8XFS, 8XFT, 8XUM, 8Y69

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 (11): 78–93, 96–104, 101–110, 113–124, 128–141, 145–187, 156–163, 196–203, 40–46, 43–52, 55–74

Glycosylation sites (1): 160

Mutagenesis-validated functional residues (2):

Position	Phenotype
105	loss of lgr5-binding, no effect on interaction with rnf43 and znrf3, no effect on wnt3a signaling; when associated with
109	loss of lgr5-binding, no effect on interaction with rnf43 and znrf3, no effect on wnt3a signaling; when associated with

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: 353 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, RNGTGGGC_UNKNOWN, GOBP_EPITHELIUM_DEVELOPMENT, ACTACCT_MIR196A_MIR196B, BENPORATH_ES_WITH_H3K27ME3, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_EPITHELIAL_TUBE_BRANCHING_INVOLVED_IN_LUNG_MORPHOGENESIS, GOBP_HINDLIMB_MORPHOGENESIS, GOBP_GROWTH, GOBP_LUNG_MORPHOGENESIS, GOCC_CELL_SURFACE, GOBP_OSTEOBLAST_DIFFERENTIATION, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY

GO Biological Process (14): osteoblast differentiation (GO:0001649), positive regulation of Wnt signaling pathway (GO:0030177), bone mineralization (GO:0030282), embryonic forelimb morphogenesis (GO:0035115), embryonic hindlimb morphogenesis (GO:0035116), negative regulation of odontogenesis of dentin-containing tooth (GO:0042489), canonical Wnt signaling pathway (GO:0060070), limb development (GO:0060173), lung growth (GO:0060437), epithelial tube branching involved in lung morphogenesis (GO:0060441), trachea cartilage morphogenesis (GO:0060535), dopaminergic neuron differentiation (GO:0071542), positive regulation of canonical Wnt signaling pathway (GO:0090263), Wnt signaling pathway (GO:0016055)

GO Molecular Function (4): signaling receptor binding (GO:0005102), heparin binding (GO:0008201), BMP receptor binding (GO:0070700), protein binding (GO:0005515)

GO Cellular Component (3): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cell surface (GO:0009986)

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
ossification	2
Wnt signaling pathway	2
embryonic limb morphogenesis	2
cellular anatomical structure	2
cell differentiation	1
positive regulation of signal transduction	1
regulation of Wnt signaling pathway	1
biomineral tissue development	1
forelimb morphogenesis	1
hindlimb morphogenesis	1
odontogenesis of dentin-containing tooth	1
negative regulation of odontogenesis	1
regulation of odontogenesis of dentin-containing tooth	1
appendage development	1
lung development	1
organ growth	1
branching morphogenesis of an epithelial tube	1
lung morphogenesis	1
trachea morphogenesis	1
trachea cartilage development	1
cartilage morphogenesis	1
neuron differentiation	1
positive regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
cell surface receptor signaling pathway	1
protein binding	1
glycosaminoglycan binding	1
sulfur compound binding	1
transmembrane receptor protein serine/threonine kinase binding	1
binding	1

Protein interactions and networks

STRING

1967 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RSPO2	LGR4	Q9BXB1	951
RSPO2	LGR5	O75473	918
RSPO2	KRT71	Q3SY84	910
RSPO2	ZNRF3	Q9ULT6	881
RSPO2	RNF43	Q68DV7	877
RSPO2	PTPRK	Q15262	791
RSPO2	FGF5	P12034	706
RSPO2	LGR6	Q9HBX8	637
RSPO2	EIF3E	P60228	608
RSPO2	CTNNB1	P35222	598
RSPO2	WNT3A	P56704	595
RSPO2	AXIN2	Q9Y2T1	575
RSPO2	DVL1	O14640	566
RSPO2	PDIK1L	Q8N165	560
RSPO2	MAP3K21	Q5TCX8	558

IntAct

19 interactions, top by confidence:

A	B	Type	Score
RSPO2	KRTAP10-4	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-7	RSPO2	psi-mi:“MI:0915”(physical association)	0.560
RSPO2	KRTAP10-9	psi-mi:“MI:0915”(physical association)	0.560
	RSPO2	psi-mi:“MI:0915”(physical association)	0.560
RSPO2	PLEKHF2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-4	RSPO2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-9	RSPO2	psi-mi:“MI:0915”(physical association)	0.560
RSPO2		psi-mi:“MI:0915”(physical association)	0.560
PLEKHF2	RSPO2	psi-mi:“MI:0915”(physical association)	0.560
RSPO2	PPIB	psi-mi:“MI:0915”(physical association)	0.400
SUV39H1	RSPO2	psi-mi:“MI:0915”(physical association)	0.370
JMJD6	RSPO2	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (38): RSPO2 (Two-hybrid), KRTAP10-4 (Two-hybrid), KRTAP10-7 (Two-hybrid), KRTAP10-9 (Two-hybrid), KRTAP10-1 (Two-hybrid), ZNRF3 (FRET), RSPO2 (Reconstituted Complex), RSPO2 (Reconstituted Complex), FZD7 (Affinity Capture-Western), ZNRF3 (Affinity Capture-Western), RSPO2 (Affinity Capture-Western), RSPO2 (Reconstituted Complex), RSPO2 (Reconstituted Complex), LGR5 (Affinity Capture-Western), RSPO2 (Affinity Capture-Western)

ESM2 similar proteins: A7MBS7, D3YXF5, F1LW30, O89103, P10643, P11680, P27918, P35446, P82987, P90884, Q29RQ1, Q2I0M5, Q2MKA7, Q3UPR9, Q3UTY6, Q4R7Z5, Q5M7L6, Q5RAD0, Q5RBP1, Q5RBP8, Q5UE90, Q64181, Q66PY1, Q69ZU6, Q6NZL8, Q6P4U0, Q6UXX9, Q6ZMP0, Q7T3Q2, Q7TSK7, Q80YN4, Q86TH1, Q8BFU0, Q8BJ73, Q8BLI0, Q8IUX8, Q8IWY4, Q8IX30, Q8N6G6, Q8VCC9

Diamond homologs: A7MBS7, P41413, Q04592, Q1RMU1, Q2I0M5, Q2MKA7, Q2TJ95, Q5M7L6, Q5R328, Q5UE90, Q69ZU6, Q6DHR0, Q6P4U0, Q6UXX9, Q8BFU0, Q8BJ73, Q92824, Q9BXY4, Q9C0I4, Q9UPZ6, Q9Z132, P35446, P30432, P35447, P51559, Q8BMS2, Q8VCC9, Q9BUD6, Q9GLX9, Q9HCB6, Q9WV75, P24062, P29122, Q63415

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
RSPO2	up-regulates	SDC4	binding
RSPO2	up-regulates	LGR4	binding
RSPO2	up-regulates	LGR5	binding
RSPO2	“down-regulates quantity”	FZD4	ubiquitination

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — COADREAD.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	2
Uncertain significance	45
Likely benign	32
Benign	8

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
1974110	NM_178565.5(RSPO2):c.256C>T (p.Arg86Ter)	Pathogenic
545633	NM_178565.5(RSPO2):c.409G>T (p.Glu137Ter)	Pathogenic
545634	NM_178565.5(RSPO2):c.205C>T (p.Arg69Cys)	Pathogenic
686219	GRCh37/hg19 8q23.1(chr8:109005377-109197390)x1	Pathogenic
3780569	NM_178565.5(RSPO2):c.95-1G>A	Likely pathogenic
545632	NM_178565.5(RSPO2):c.125del (p.Gly42fs)	Likely pathogenic

SpliceAI

1723 predictions. Top by Δscore:

Variant	Effect	Δscore
8:107901186:CTTCC:C	acceptor_gain	1.0000
8:107901187:TTCC:T	acceptor_gain	1.0000
8:107901188:TCC:T	acceptor_gain	1.0000
8:107901189:CC:C	acceptor_gain	1.0000
8:107901189:CCC:C	acceptor_gain	1.0000
8:107901190:CC:C	acceptor_gain	1.0000
8:107901191:C:CC	acceptor_gain	1.0000
8:107901191:CTG:C	acceptor_loss	1.0000
8:107901196:A:AC	acceptor_gain	1.0000
8:107901196:A:C	acceptor_gain	1.0000
8:107958264:TCCTT:T	acceptor_gain	1.0000
8:107958265:CCTTC:C	acceptor_gain	1.0000
8:107958272:G:GC	acceptor_gain	1.0000
8:107958279:T:C	acceptor_gain	1.0000
8:107958279:T:TC	acceptor_gain	1.0000
8:107958280:T:C	acceptor_gain	1.0000
8:107958280:T:TC	acceptor_gain	1.0000
8:107958282:T:C	acceptor_gain	1.0000
8:107958282:T:TC	acceptor_gain	1.0000
8:107960668:ACT:A	donor_loss	1.0000
8:107960669:CTC:C	donor_loss	1.0000
8:107960670:T:TC	donor_loss	1.0000
8:107960671:CAC:C	donor_loss	1.0000
8:107960672:A:AC	donor_gain	1.0000
8:107960672:A:AG	donor_loss	1.0000
8:107960672:AC:A	donor_gain	1.0000
8:107960673:C:CC	donor_gain	1.0000
8:107960673:CC:C	donor_gain	1.0000
8:107960673:CCCA:C	donor_gain	1.0000
8:107960825:CAATT:C	acceptor_gain	1.0000

AlphaMissense

1622 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:107958175:C:G	R174P	1.000
8:107958181:C:G	R172T	1.000
8:107958237:C:A	W153C	1.000
8:107958237:C:G	W153C	1.000
8:107958246:C:A	W150C	1.000
8:107958246:C:G	W150C	1.000
8:107960771:A:C	C110W	1.000
8:107989118:C:G	C74S	1.000
8:107989119:A:G	C74R	1.000
8:107989119:A:T	C74S	1.000
8:107989175:C:G	C55S	1.000
8:107989176:A:T	C55S	1.000
8:107989184:C:G	C52S	1.000
8:107989185:A:T	C52S	1.000
8:107989187:C:T	G51E	1.000
8:107958108:G:C	C196W	0.999
8:107958109:C:G	C196S	0.999
8:107958110:A:T	C196S	0.999
8:107958180:T:A	R172S	0.999
8:107958180:T:G	R172S	0.999
8:107958181:C:A	R172I	0.999
8:107958193:C:T	G168D	0.999
8:107958194:C:G	G168R	0.999
8:107958228:A:C	C156W	0.999
8:107958229:C:G	C156S	0.999
8:107958229:C:T	C156Y	0.999
8:107958230:A:G	C156R	0.999
8:107958230:A:T	C156S	0.999
8:107958239:A:G	W153R	0.999
8:107958239:A:T	W153R	0.999

dbSNP variants (sampled 300 via entrez): RS1000019993 (8:107964754 C>G), RS1000023527 (8:107907230 T>C), RS1000023825 (8:107995564 C>G,T), RS1000052999 (8:108013689 T>C), RS1000053275 (8:108042507 C>T), RS1000090692 (8:108042239 G>A), RS1000115576 (8:107972179 T>G), RS1000124326 (8:107919176 G>A,T), RS1000126817 (8:107914196 G>A,T), RS1000134075 (8:107983981 C>G), RS1000150337 (8:108032586 C>T), RS1000164937 (8:107935685 T>A,C), RS1000182048 (8:108081105 CG>C), RS1000188120 (8:107945500 G>A,T), RS1000190916 (8:108072645 G>A)

Disease associations

OMIM: gene MIM:610575 | disease phenotypes: MIM:618021, MIM:618022, MIM:273395

GenCC curated gene-disease

Disease	Classification	Inheritance
tetraamelia syndrome 2	Strong	Autosomal recessive
tetraamelia-multiple malformations syndrome	Supportive	Autosomal recessive

Mondo (3): tetraamelia syndrome 2 (MONDO:0060732), humerofemoral hypoplasia with radiotibial ray deficiency (MONDO:0060733), tetraamelia-multiple malformations syndrome (MONDO:0010110)

Orphanet (1): Tetraamelia-multiple malformations syndrome (Orphanet:3301)

HPO phenotypes

61 total (30 of 61 shown, HPO-id order):

HPO	Term
HP:0000003	Multicystic kidney dysplasia
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000046	Small scrotum
HP:0000054	Micropenis
HP:0000148	Vaginal atresia
HP:0000160	Narrow mouth
HP:0000162	Glossoptosis
HP:0000175	Cleft palate
HP:0000202	Orofacial cleft
HP:0000238	Hydrocephalus
HP:0000278	Retrognathia
HP:0000293	Full cheeks
HP:0000308	Microretrognathia
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000482	Microcornea
HP:0000518	Cataract
HP:0000568	Microphthalmia
HP:0000612	Iris coloboma
HP:0000648	Optic atrophy
HP:0000772	Abnormal rib morphology
HP:0000776	Congenital diaphragmatic hernia
HP:0000882	Hypoplastic scapulae
HP:0000894	Short clavicles
HP:0000921	Missing ribs
HP:0001274	Agenesis of corpus callosum
HP:0001561	Polyhydramnios
HP:0001600	Abnormality of the larynx

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST001144_5	Dupuytren’s disease	8.000000e-15
GCST001320_8	Acute lymphoblastic leukemia (childhood)	2.000000e-06
GCST002545_2	Ossification of the posterior longitudinal ligament of the spine	2.000000e-13
GCST004858_11	Dupuytren’s disease	1.000000e-32
GCST005116_12	Male-pattern baldness	2.000000e-22
GCST005116_37	Male-pattern baldness	1.000000e-16
GCST005116_38	Male-pattern baldness	2.000000e-14
GCST006585_2646	Blood protein levels	2.000000e-07
GCST006661_142	Male-pattern baldness	6.000000e-19
GCST006661_172	Male-pattern baldness	2.000000e-11
GCST006661_282	Male-pattern baldness	5.000000e-27
GCST006976_78	Macular thickness	2.000000e-09
GCST006979_472	Heel bone mineral density	6.000000e-14
GCST006988_165	Blond vs. brown/black hair color	1.000000e-13
GCST006988_66	Blond vs. brown/black hair color	6.000000e-10
GCST008156_41	Hip circumference adjusted for BMI	9.000000e-07
GCST008759_5	Intake of total sugars	2.000000e-06
GCST010703_291	Brain morphology (MOSTest)	9.000000e-15
GCST012282_7	BMI x environmental factors (excluding physical activity) interaction	4.000000e-06

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0004229	Dupuytren Contracture
EFO:0009270	heel bone mineral density
EFO:0003924	hair color
EFO:0008039	BMI-adjusted hip circumference
EFO:0010158	sugar consumption measurement
EFO:0004346	neuroimaging measurement
EFO:0004340	body mass index
EFO:0006527	smoking status measurement
EFO:0009374	energy intake measurement
EFO:0009695	household income
EFO:0010810	protein intake measurement
EFO:0010811	carbohydrate intake measurement
EFO:0011015	educational attainment

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C536500	Tetraamelia multiple malformations (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, decreases methylation, affects cotreatment	7
methylmercuric chloride	decreases expression, increases expression	3
trichostatin A	affects cotreatment, decreases expression	3
Benzo(a)pyrene	affects methylation, decreases expression, increases expression, increases methylation	3
mercuric bromide	decreases expression, affects cotreatment	2
entinostat	decreases expression, affects cotreatment	2
Resveratrol	affects cotreatment, decreases expression	2
Panobinostat	affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Aflatoxin B1	decreases expression, decreases methylation	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
decabromobiphenyl ether	decreases expression	1
arsenite	increases methylation	1
tetrabromobisphenol A	decreases expression	1
ferrous chloride	increases expression	1
tetrachlorodian	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	affects cotreatment, decreases methylation	1
theaflavin-3,3’-digallate	affects expression	1
Arsenic Trioxide	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Vorinostat	decreases expression	1
Acetaminophen	decreases expression	1
Copper	affects cotreatment, decreases expression	1
Cytarabine	decreases expression	1
Malathion	decreases expression	1
Melphalan	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Okadaic Acid	increases expression	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8P1	Abcam HCT 116 RSPO2 KO	Cancer cell line	Male
CVCL_B9BB	Abcam MCF-7 RSPO2 KO	Cancer cell line	Female
CVCL_B9RD	Abcam A-549 RSPO2 KO	Cancer cell line	Male
CVCL_D7ZQ	Ubigene A-549 RSPO2 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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