RSPO3

Summary

RSPO3 (R-spondin 3, HGNC:20866) is a protein-coding gene on chromosome 6q22.33, encoding R-spondin-3 (Q9BXY4). Activator of the canonical Wnt signaling pathway by acting as a ligand for LGR4-6 receptors, which acts as a key regulator of angiogenesis.

This gene belongs to the R-spondin family. The encoded protein plays a role in the regulation of Wnt (wingless-type MMTV integration site family)/beta-catenin and Wnt/planar cell polarity (PCP) signaling pathways, which are involved in development, cell growth and disease pathogenesis. Genome-wide association studies suggest a correlation of this gene with bone mineral density and risk of fracture. This gene may be involved in tumor development.

Source: NCBI Gene 84870 — RefSeq curated summary.

At a glance

• GWAS associations: 361
• Clinical variants (ClinVar): 36 total
• Druggable target: yes
• MANE Select transcript: NM_032784

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20866
Approved symbol	RSPO3
Name	R-spondin 3
Location	6q22.33
Locus type	gene with protein product
Status	Approved
Aliases	FLJ14440
Ensembl gene	ENSG00000146374
Ensembl biotype	protein_coding
OMIM	610574
Entrez	84870

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000356698, ENST00000368317, ENST00000485757, ENST00000858748

RefSeq mRNA: 1 — MANE Select: NM_032784 NM_032784

CCDS: CCDS5135

Canonical transcript exons

ENST00000356698 — 5 exons

Exon	Start	End
ENSE00001007592	127155241	127155438
ENSE00001359680	127195823	127199481
ENSE00001858691	127118671	127119289
ENSE00003551533	127148648	127148839
ENSE00003571160	127150426	127150572

Expression profiles

Bgee: expression breadth ubiquitous, 218 present calls, max score 95.91.

FANTOM5 (CAGE): breadth broad, TPM avg 9.0329 / max 634.5999, expressed in 682 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
69707	8.0541	665
69708	0.9732	308
204197	0.0056	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of stomach	UBERON:0001199	95.91	gold quality
cauda epididymis	UBERON:0004360	94.90	gold quality
caput epididymis	UBERON:0004358	93.94	gold quality
smooth muscle tissue	UBERON:0001135	93.37	gold quality
corpus epididymis	UBERON:0004359	92.39	gold quality
vastus lateralis	UBERON:0001379	92.16	gold quality
superficial temporal artery	UBERON:0001614	92.02	gold quality
buccal mucosa cell	CL:0002336	90.78	gold quality
quadriceps femoris	UBERON:0001377	90.63	gold quality
placenta	UBERON:0001987	90.20	gold quality
body of uterus	UBERON:0009853	89.59	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	89.55	gold quality
seminal vesicle	UBERON:0000998	89.13	gold quality
myometrium	UBERON:0001296	88.85	gold quality
lower esophagus muscularis layer	UBERON:0035833	88.80	gold quality
lower esophagus	UBERON:0013473	88.74	gold quality
tibia	UBERON:0000979	88.56	gold quality
biceps brachii	UBERON:0001507	88.15	gold quality
deltoid	UBERON:0001476	87.71	gold quality
skeletal muscle tissue	UBERON:0001134	87.70	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	87.63	gold quality
vena cava	UBERON:0004087	87.61	gold quality
parietal pleura	UBERON:0002400	87.57	gold quality
adipose tissue of abdominal region	UBERON:0007808	87.10	gold quality
omental fat pad	UBERON:0010414	86.95	gold quality
peritoneum	UBERON:0002358	86.92	gold quality
vermiform appendix	UBERON:0001154	85.70	gold quality
cardia of stomach	UBERON:0001162	85.61	gold quality
hindlimb stylopod muscle	UBERON:0004252	84.90	gold quality
muscle tissue	UBERON:0002385	84.78	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-HCAD-5	yes	1722.65
E-GEOD-75140	yes	995.16
E-HCAD-56	yes	636.98
E-MTAB-10662	yes	400.48
E-MTAB-3929	yes	346.93
E-MTAB-6701	yes	54.74
E-HCAD-9	yes	16.19
E-ANND-3	yes	10.00
E-MTAB-8060	no	1076.35

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NKX2-5, RUNX1

miRNA regulators (miRDB)

167 targeting RSPO3, 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-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
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-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-5688	99.96	73.23	4504
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505

Literature-anchored findings (GeneRIF, showing 31)

• the gene is a novel member of thrombospondin type I repeat supergene family (hPWTSR) (PMID:12463421)
• 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)
• 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 aberrant RSPO3-LGR4 signaling potentially acts as a driving mechanism in the aggressiveness of Keap1-deficient lung ADs. (PMID:25531322)
• A genome-wide association study of bone mineral density (BMD) found a new BMD locus that harbors the PTCH1 gene, that associates with reduced spine BMD and the RSPO3 associates with increased spine BMD. (PMID:26733130)
• High RSPO3 expression is associated with breast cancer. (PMID:26735887)
• PTPRK-RSPO3 fusions and RNF43 mutations were found to be characteristic genetic features of traditional serrated adenomas (TSAs). (PMID:26924569)
• Using C-mannosylation-defective Rspo3 mutant-overexpressing cell lines, we found that C-mannosylation of Rspo3 promotes its secretion and activates Wnt/beta-catenin signaling. (PMID:27350215)
• RSPOs facilitate HSC activation and promote liver fibrogenesis by enhancing the Wnt pathway (PMID:27572318)
• Colorectal cancer cell lines identified VACO6 cells as a carrier of a canonical PTPRK(e1)-RSPO3(e2) fusion; cell line displayed marked in vitro and in vivo sensitivity to WNT blockade by the porcupine inhibitor LGK974. Long-term treatment of VACO6 cells with LGK974 led to the emergence of a resistant population carrying two frameshift deletions of the WNT pathway inhibitor AXIN1, with consequent protein loss. (PMID:28100566)
• Knockdown of RSPO3 resulted in significantly increased mRNA expression levels of RUNX2, ALP and OCN and no effects on the proliferation of human adipose-derived stem cells. (PMID:28220828)
• The present study identified RSPO fusion transcripts, including three novel transcripts, in one-third of colorectal Traditional serrated adenoma (TSA) and showed that PTPRK-RSPO3 fusions were the predominant cause of RSPO overexpression in colorectal TSA. (PMID:28543708)
• For liver transplant-free survival, a genome-wide significant signal was identified and expression of the candidate gene RSPO3 was demonstrated in key liver-resident effector cells and may play a role in primary sclerosing cholangitis disease progression. (PMID:28779025)
• RSPO3 is produced by stromal cells in the tumor microenvironment and the activating mutations appear to sensitize the tumors to Wnt-Rspo synergy. The combination of RSPO3 inhibition and taxane treatment provides an approach to effectively target oncogenic WNT signaling (PMID:29127379)
• significant association of the RSPO3 rs7741021 SNP with the calcaneus bone density (PMID:29230809)
• Taken together, we show in this short report that the matricellular protein RSPO3 is a novel permeability factor inducing barrier dysfunction in human primary vascular endothelial monolayers of macro- and micro- vascular origin, and RSPO3 acts synergistically with the prototypic pro-inflammatory mediator IL-1beta. (PMID:30157748)
• RSPO3 exhibited a tumor-promoting effect in bladder cancer cells through activation of Wnt/beta-catenin and Hedgehog signaling pathways. (PMID:30329043)
• RSPO3 functions as a positive prognostic marker in prostate cancer. (PMID:30987640)
• RSPO3 promotes the tumor growth and progression of choriocarcinoma. (PMID:31851527)
• Elevated levels of the secreted wingless agonist R-spondin 3 in preeclamptic pregnancies. (PMID:31990902)
• RSPO3 was found to be highly elevated in the active lesions of fibrotic tissues in patients with idiopathic pulmonary fibrosis and nonalcoholic steatohepatitis. (PMID:32160239)
• R-spondins engage heparan sulfate proteoglycans to potentiate WNT signaling. (PMID:32432544)
• RSPO3 impacts body fat distribution and regulates adipose cell biology in vitro. (PMID:32493999)
• Targeting RSPO3-LGR4 Signaling for Leukemia Stem Cell Eradication in Acute Myeloid Leukemia. (PMID:32559496)
• R-Spondins 2 and 3 Are Overexpressed in a Subset of Human Colon and Breast Cancers. (PMID:33320737)
• RSPO3 is important for trabecular bone and fracture risk in mice and humans. (PMID:34389713)
• RSPO3 is a novel contraction-inducible factor identified in an ““in vitro exercise model”” using primary human myotubes. (PMID:35995979)
• Investigation of cell signalings and therapeutic targets in PTPRK-RSPO3 fusion-positive colorectal cancer. (PMID:36129915)
• Amniotic fluid stem cell attenuated necrotizing enterocolitis progression by promoting Rspo3/AMPKalpha axis. (PMID:37173190)
• Upregulation of RSPO3 via targeted promoter DNA demethylation inhibits the progression of cholangiocarcinoma. (PMID:37932819)
• RSPO3 regulates the radioresistance of Non-Small cell lung cancer cells via NLRP3 Inflammasome-Mediated pyroptosis. (PMID:39245068)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	rspo3	ENSDARG00000070081
mus_musculus	Rspo3	ENSMUSG00000019880
rattus_norvegicus	Rspo3	ENSRNOG00000011568

Paralogs (3): RSPO4 (ENSG00000101282), RSPO2 (ENSG00000147655), RSPO1 (ENSG00000169218)

Protein

Protein identifiers

R-spondin-3 — Q9BXY4 (reviewed: Q9BXY4)

Alternative names: Protein with TSP type-1 repeat, Roof plate-specific spondin-3, Thrombospondin type-1 domain-containing protein 2

All UniProt accessions (1): Q9BXY4

UniProt curated annotations — full annotation on UniProt →

Function. Activator of the canonical Wnt signaling pathway by acting as a ligand for LGR4-6 receptors, which acts as a key regulator of angiogenesis. 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. Acts as a ligand for frizzled FZD8 and LRP6. May negatively regulate the TGF-beta pathway. Acts as a key regulator of angiogenesis by controlling vascular stability and pruning: acts by activating the non-canonical Wnt signaling pathway in endothelial cells. Can also amplify Wnt signaling pathway independently of LGR4-6 receptors, possibly by acting as a direct antagonistic ligand to RNF43 and ZNRF3.

Subunit / interactions. Interacts with the extracellular domain of FZD8 and LRP6. It however does not form a ternary complex with FZD8 and LRP6. Interacts with WNT1. Binds heparin. Interacts with LGR4, LGR5 and LGR6.

Subcellular location. Secreted.

Tissue specificity. Ubiquitously expressed. Expressed at higher level in placenta, small intestine, fetal thymus and lymph node. Highly expressed in endothelial cells.

Domain organisation. The FU repeats are required for activation and stabilization of beta-catenin.

Similarity. Belongs to the R-spondin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BXY4-1	1	yes
Q9BXY4-2	2

RefSeq proteins (1): NP_116173* (*=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
IPR044004	TSP1_spondin_dom	Domain
IPR051514	R-spondin	Family

Pfam: PF15913, PF19028

UniProt features (25 total): disulfide bond 11, repeat 2, mutagenesis site 2, sequence conflict 2, compositionally biased region 2, signal peptide 1, chain 1, splice variant 1, domain 1, region of interest 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BXY4-F1	78.27	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 (11): 45–54, 57–76, 80–95, 98–105, 102–111, 114–125, 129–142, 148–190, 159–166, 199–206, 41–48

Glycosylation sites (1): 36

Mutagenesis-validated functional residues (2):

Position	Phenotype
106	loss of lgr4/5/6-binding, no effect on wnt3a signaling; when associated with a-110.
110	loss of lgr4/5/6-binding, no effect on wnt3a signaling; when associated with a-106.

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-4641263	Regulation of FZD by ubiquitination
R-HSA-8939256	RUNX1 regulates transcription of genes involved in WNT signaling
R-HSA-162582	Signal Transduction
R-HSA-195721	Signaling by WNT
R-HSA-201681	TCF dependent signaling in response to WNT
R-HSA-212436	Generic Transcription Pathway
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8878171	Transcriptional regulation by RUNX1

MSigDB gene sets: 161 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_LABYRINTHINE_LAYER_DEVELOPMENT, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_NON_CANONICAL_WNT_SIGNALING_PATHWAY, GOBP_REGULATION_OF_NON_CANONICAL_WNT_SIGNALING_PATHWAY, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, BONCI_TARGETS_OF_MIR15A_AND_MIR16_1, GOBP_EMBRYONIC_PLACENTA_DEVELOPMENT, PICCALUGA_ANGIOIMMUNOBLASTIC_LYMPHOMA_UP, GOBP_SPROUTING_ANGIOGENESIS, GOBP_IN_UTERO_EMBRYONIC_DEVELOPMENT, GOBP_CANONICAL_WNT_SIGNALING_PATHWAY

GO Biological Process (10): blood vessel remodeling (GO:0001974), sprouting angiogenesis (GO:0002040), positive regulation of Wnt signaling pathway (GO:0030177), canonical Wnt signaling pathway (GO:0060070), branching involved in labyrinthine layer morphogenesis (GO:0060670), positive regulation of canonical Wnt signaling pathway (GO:0090263), positive regulation of non-canonical Wnt signaling pathway (GO:2000052), positive regulation of Wnt signaling pathway, planar cell polarity pathway (GO:2000096), angiogenesis (GO:0001525), Wnt signaling pathway (GO:0016055)

GO Molecular Function (3): signaling receptor binding (GO:0005102), frizzled binding (GO:0005109), heparin binding (GO:0008201)

GO Cellular Component (2): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
TCF dependent signaling in response to WNT	1
Transcriptional regulation by RUNX1	1
Signal Transduction	1
Signaling by WNT	1
RNA Polymerase II Transcription	1
Gene expression (Transcription)	1
Generic Transcription Pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
Wnt signaling pathway	2
positive regulation of Wnt signaling pathway	2
tissue remodeling	1
angiogenesis	1
positive regulation of signal transduction	1
regulation of Wnt signaling pathway	1
embryonic morphogenesis	1
labyrinthine layer morphogenesis	1
morphogenesis of a branching epithelium	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
non-canonical Wnt signaling pathway	1
regulation of non-canonical Wnt signaling pathway	1
Wnt signaling pathway, planar cell polarity pathway	1
positive regulation of non-canonical Wnt signaling pathway	1
regulation of Wnt signaling pathway, planar cell polarity pathway	1
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
cell surface receptor signaling pathway	1
protein binding	1
G protein-coupled receptor binding	1
glycosaminoglycan binding	1
sulfur compound binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1992 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RSPO3	LGR4	Q9BXB1	977
RSPO3	LGR5	O75473	878
RSPO3	SDC4	P31431	845
RSPO3	WNT3A	P56704	772
RSPO3	FURIN	P09958	739
RSPO3	CTNNB1	P35222	726
RSPO3	ZNRF3	Q9ULT6	725
RSPO3	FZD8	Q9H461	722
RSPO3	PTPRK	Q15262	700
RSPO3	RNF43	Q68DV7	698
RSPO3	LRP6	O75581	652
RSPO3	FZD7	O75084	632
RSPO3	WNT1	P04628	605
RSPO3	LGR6	Q9HBX8	599
RSPO3	PORCN	Q9H237	598

IntAct

7 interactions, top by confidence:

A	B	Type	Score
RSPO3	HSPA5	psi-mi:“MI:0915”(physical association)	0.400
RSPO3	DPY19L3	psi-mi:“MI:0915”(physical association)	0.400
M		psi-mi:“MI:0914”(association)	0.350
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350
EEA1	RSPO3	psi-mi:“MI:0403”(colocalization)	0.270
RSPO3	lgr4	psi-mi:“MI:0403”(colocalization)	0.270

BioGRID (13): ZNRF3 (FRET), RSPO3 (Reconstituted Complex), RSPO3 (Reconstituted Complex), DPY19L3 (Affinity Capture-MS), RSPO3 (Reconstituted Complex), RSPO3 (Reconstituted Complex), RSPO3 (Protein-RNA), RSPO3 (Reconstituted Complex), RSPO3 (Affinity Capture-Western), RSPO3 (Proximity Label-MS), DPY19L3 (Affinity Capture-MS), RSPO3 (Affinity Capture-MS), LGR4 (FRET)

ESM2 similar proteins: A5A6L1, A7E2Z9, A8MWY0, F1R520, O00622, O93390, O94985, P07214, P09486, P12025, P13213, P16975, P18406, P19336, P20112, P21246, P21741, P21782, P24052, P24593, P24594, P31515, P32760, P33005, P36377, P36378, P48530, P48531, P48532, P48533, P63089, P63090, P79281, Q05717, Q07079, Q1RMU1, Q28985, Q2TJ95, Q3UZV7, Q5R767

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, B3EWY9, B3EWZ8, D3YXG0, P35442, P79331, Q03350, Q32L50, Q3UPR9, Q69Z28

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
RSPO3	up-regulates	SDC4	binding
RSPO3	up-regulates	LGR5	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	29
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1121 predictions. Top by Δscore:

Variant	Effect	Δscore
6:127148634:A:AG	acceptor_gain	1.0000
6:127148635:T:G	acceptor_gain	1.0000
6:127148645:CA:C	acceptor_loss	1.0000
6:127148646:A:AG	acceptor_gain	1.0000
6:127148646:AGT:A	acceptor_gain	1.0000
6:127148646:AGTGC:A	acceptor_loss	1.0000
6:127148647:G:GC	acceptor_gain	1.0000
6:127148647:GT:G	acceptor_gain	1.0000
6:127148647:GTG:G	acceptor_gain	1.0000
6:127148647:GTGC:G	acceptor_gain	1.0000
6:127148833:TGTAC:T	donor_gain	1.0000
6:127148836:ACAAG:A	donor_loss	1.0000
6:127148838:AAGTA:A	donor_loss	1.0000
6:127148839:AGT:A	donor_loss	1.0000
6:127148840:G:GG	donor_gain	1.0000
6:127148840:G:T	donor_loss	1.0000
6:127148841:T:A	donor_loss	1.0000
6:127150422:TCA:T	acceptor_loss	1.0000
6:127150423:CA:C	acceptor_loss	1.0000
6:127150424:A:AG	acceptor_gain	1.0000
6:127150424:AGAAT:A	acceptor_gain	1.0000
6:127150425:G:GT	acceptor_gain	1.0000
6:127150425:GA:G	acceptor_gain	1.0000
6:127150425:GAA:G	acceptor_gain	1.0000
6:127150425:GAAT:G	acceptor_gain	1.0000
6:127150425:GAATG:G	acceptor_gain	1.0000
6:127150573:G:GG	donor_gain	1.0000
6:127155413:G:GT	donor_gain	1.0000
6:127195817:TTTCA:T	acceptor_loss	1.0000
6:127195818:TTCA:T	acceptor_loss	1.0000

AlphaMissense

1796 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:127148708:G:A	G53E	1.000
6:127148710:T:A	C54S	1.000
6:127148711:G:C	C54S	1.000
6:127148719:T:A	C57S	1.000
6:127148720:G:A	C57Y	1.000
6:127148720:G:C	C57S	1.000
6:127148776:T:A	C76S	1.000
6:127148776:T:C	C76R	1.000
6:127148777:G:A	C76Y	1.000
6:127148777:G:C	C76S	1.000
6:127148778:T:G	C76W	1.000
6:127148683:T:A	C45S	0.999
6:127148684:G:C	C45S	0.999
6:127148692:T:A	C48S	0.999
6:127148693:G:C	C48S	0.999
6:127148695:T:C	S49P	0.999
6:127148706:T:A	N52K	0.999
6:127148706:T:G	N52K	0.999
6:127148707:G:A	G53R	0.999
6:127148707:G:C	G53R	0.999
6:127148708:G:T	G53V	0.999
6:127148710:T:C	C54R	0.999
6:127148712:T:G	C54W	0.999
6:127148719:T:C	C57R	0.999
6:127148720:G:T	C57F	0.999
6:127148721:T:G	C57W	0.999
6:127148734:T:C	F62L	0.999
6:127148735:T:C	F62S	0.999
6:127148735:T:G	F62C	0.999
6:127148736:T:A	F62L	0.999

dbSNP variants (sampled 300 via entrez): RS1000011202 (6:127177624 T>C), RS1000043570 (6:127121072 T>C), RS1000077788 (6:127120891 C>A), RS1000086184 (6:127166773 C>T), RS1000204250 (6:127138063 C>G), RS1000302666 (6:127147692 C>A), RS1000334156 (6:127148031 A>G,T), RS1000353455 (6:127134516 T>C), RS1000388728 (6:127140587 C>T), RS1000433588 (6:127188471 G>A,C), RS1000459987 (6:127167121 T>G), RS1000484058 (6:127188847 T>C), RS1000546558 (6:127181690 A>G), RS1000564311 (6:127155724 A>G), RS1000629615 (6:127127643 C>T)

Disease associations

OMIM: gene MIM:610574 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

361 associations (top):

Study	Trait	p-value
GCST000302_3	Iron status biomarkers	2.000000e-06
GCST000829_12	Waist-hip ratio	2.000000e-40
GCST001050_2	Bone mineral density	3.000000e-08
GCST001233_15	Metabolite levels	1.000000e-08
GCST001483_1	Intracranial volume	2.000000e-13
GCST001610_14	Renal function-related traits (BUN)	1.000000e-11
GCST001954_2	Waist-hip ratio	9.000000e-10
GCST002143_4	Blood pressure	3.000000e-10
GCST002143_8	Blood pressure	2.000000e-11
GCST002216_5	Triglycerides	3.000000e-08
GCST002223_49	HDL cholesterol	3.000000e-10
GCST002333_2	Bone properties (heel)	1.000000e-19
GCST002334_1	Bone properties (heel)	4.000000e-08
GCST002335_3	Bone properties (heel)	9.000000e-21
GCST002493_2	Bone mineral density (paediatric, skull)	3.000000e-11
GCST002493_3	Bone mineral density (paediatric, skull)	1.000000e-06
GCST002493_4	Bone mineral density (paediatric, skull)	4.000000e-11
GCST002494_9	Bone mineral density (paediatric, total body less head)	2.000000e-06
GCST002496_1	Bone mineral density (paediatric, upper limb)	3.000000e-09
GCST002496_6	Bone mineral density (paediatric, upper limb)	4.000000e-08
GCST002756_9	Subcortical brain region volumes	9.000000e-06
GCST002782_161	Waist-to-hip ratio adjusted for body mass index	2.000000e-19
GCST002782_162	Waist-to-hip ratio adjusted for body mass index	2.000000e-06
GCST002782_163	Waist-to-hip ratio adjusted for body mass index	3.000000e-22
GCST002782_164	Waist-to-hip ratio adjusted for body mass index	1.000000e-06
GCST002782_165	Waist-to-hip ratio adjusted for body mass index	3.000000e-19
GCST002782_166	Waist-to-hip ratio adjusted for body mass index	7.000000e-23
GCST002782_252	Waist-to-hip ratio adjusted for body mass index	4.000000e-30
GCST002782_253	Waist-to-hip ratio adjusted for body mass index	3.000000e-10
GCST002782_254	Waist-to-hip ratio adjusted for body mass index	4.000000e-35

EFO canonical traits (49, from GWAS)

EFO ID	Trait name
EFO:0004461	iron biomarker measurement
EFO:0004343	waist-hip ratio
EFO:0004761	uric acid measurement
EFO:0004886	intracranial volume measurement
EFO:0006335	systolic blood pressure
EFO:0006336	diastolic blood pressure
EFO:0004530	triglyceride measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0005654	velocity of sound measurement
EFO:0004514	bone quantitative ultrasound measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0007701	spine bone mineral density
EFO:0007829	eating behaviour
EFO:0007830	food addiction measurement
EFO:0004458	C-reactive protein measurement
EFO:0004703	age at menarche
EFO:0007906	synophrys measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0008039	BMI-adjusted hip circumference
EFO:0004318	smoking behavior
EFO:0008002	physical activity measurement
EFO:0004305	erythrocyte count
EFO:0004509	hemoglobin measurement
EFO:0004682	QT interval
EFO:0007785	femoral neck bone mineral density
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0006340	mean arterial pressure
EFO:0004329	alcohol drinking
EFO:0006527	smoking status measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4665590 (PROTEIN-PROTEIN INTERACTION)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	3
methylmercuric chloride	decreases expression, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	increases methylation, increases mutagenesis	2
Silicon Dioxide	increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
bisphenol A	increases expression	1
N(4)-hydroxycytidine	decreases expression	1
trichostatin A	increases expression	1
sulforaphane	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	1
dorsomorphin	affects cotreatment, increases expression, decreases expression	1
bisphenol S	increases expression	1
jinfukang	decreases expression, affects cotreatment	1
Fulvestrant	increases methylation	1
Air Pollutants	decreases expression, increases abundance	1
Allergens	decreases expression	1
Carbamazepine	affects expression	1
Cisplatin	affects cotreatment, decreases expression	1
Succimer	affects cotreatment, decreases expression	1
Naled	affects expression	1
Nickel	increases expression	1
Oxygen	decreases expression	1
Pesticides	decreases methylation	1
Rifampin	decreases expression	1
Rotenone	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Triclosan	decreases expression	1
Aflatoxin B1	decreases methylation	1
Okadaic Acid	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7ZR	Ubigene A-549 RSPO3 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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