RSPO3

Chr 6

R-spondin 3

Also known as: CRISTIN1, PWTSR, THSD2

NCBI Gene: 84870ENSG00000146374UniProt: Q9BXY4

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. [provided by RefSeq, Jul 2013]

53
ClinVar variants
16
Pathogenic / LP
0.09
pLI score
1
Active trials
Clinical Summary— RSPO3
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.29) despite low pLI — interpret in context.
📋
ClinVar Variants
16 Pathogenic / Likely Pathogenic· 33 VUS of 53 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.60LOEUF
pLI 0.089
Z-score 2.75
OE 0.29 (0.15–0.60)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.02Z-score
OE missense 0.76 (0.65–0.89)
107 obs / 141.0 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.29 (0.15–0.60)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.76 (0.65–0.89)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.95
0≤1.21.6
LoF obs/exp: 5 / 17.4Missense obs/exp: 107 / 141.0Syn Z: 0.28

ClinVar Variant Classifications

53 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13
Likely Pathogenic3
VUS33
Likely Benign4
13
Pathogenic
3
Likely Pathogenic
33
VUS
4
Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
13
0
13
Likely Pathogenic
0
0
3
0
3
VUS
0
26
7
0
33
Likely Benign
0
1
3
0
4
Benign
0
0
0
0
0
Total02726053

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

RSPO3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
R-SPONDIN 3; RSPO3
MIM #610574 · *
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Decreased RSPO3 and β-Catenin in Preeclampsia: Correlation with Blood Pressure and Pregnancy Outcomes.
Liu Y et al.·Med Sci Monit
2024
Discovery of novel diagnostic biomarkers of hepatocellular carcinoma associated with immune infiltration.
Liu Q et al.·Ann Med
2025
Upregulation of RSPO3 via targeted promoter DNA demethylation inhibits the progression of cholangiocarcinoma.
Wu G et al.·Clin Epigenetics
2023
RSPO3 regulates the radioresistance of Non-Small cell lung cancer cells via NLRP3 Inflammasome-Mediated pyroptosis.
Li H et al.·Radiother Oncol
2024
R-spondin-3 promotes proliferation and invasion of breast cancer cells independently of Wnt signaling.
Ter Steege EJ et al.·Cancer Lett
2023
Identification of potential druggable targets for endometriosis through Mendelian randomization analysis.
Chen P et al.·Front Endocrinol (Lausanne)
2025
The role of R-spondin proteins in cancer biology.
Ter Steege EJ et al.·Oncogene
2021Review
Investigation of cell signalings and therapeutic targets in PTPRK-RSPO3 fusion-positive colorectal cancer.
Jeong JH et al.·PLoS One
2022
RSPO3 impairs barrier function of human vascular endothelial monolayers and synergizes with pro-inflammatory IL-1.
Skaria T et al.·Mol Med
2018
Innovate therapeutic targets for autoimmune diseases: insights from proteome-wide mendelian randomization and Bayesian colocalization.
Jin Q et al.·Autoimmunity
2024
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
NsPEFs-enriched ADSCs-EVs alleviate osteoarthritis via RSPO3-mediated dual pro-chondrogenic and pro-M2 macrophage properties.
Wang Y et al.·Bioact Mater
2026🔓 Open Access
Deletion of Rspo1 or Rspo3 in the mesenchyme does not affect Wolffian duct maintenance or morphogenesis.
Jia S et al.·MicroPubl Biol
2026🔓 Open Access
RSPO3 rearrangements in advanced colorectal cancer patients and their relationship with disease characteristics.
Tur R et al.·World J Gastrointest Oncol
2025🔓 Open AccessCohort
Regulation of RSPO3-LGR4 Signaling: Emerging Role in Inflammation Revealed by Network Analysis.
Stojanovic M et al.·Arch Clin Biomed Res
2025🔓 Open Access
H3K4me3 regulates the transcription of RSPO3 in dermal papilla cells to influence hair follicle morphogenesis and development.
Zhong Z et al.·Epigenetics Chromatin
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Metastatic Colorectal CancerMetastatic Cancer to Liver

FAPI Molecular Imaging for Diagnosis of the CMS4 Unfavorable Colorectal Cancer Subtype

NOT YET RECRUITING
NCT06191120Phase NAUMC UtrechtStarted 2024-04
[18F]-ALF-FAPI-74 PET/CT scan

External Resources

Links to major genomics databases and tools