RSPO1

Chr 1AR

R-spondin 1

Also known as: CRISTIN3, RSPO

NCBI Gene: 284654ENSG00000169218UniProt: Q2MKA7OMIM: 609595

The protein functions as a secreted activator that binds to LGR4-6 receptors to positively regulate the canonical Wnt signaling pathway and plays an essential role in ovary determination. Mutations cause autosomal recessive palmoplantar hyperkeratosis with sex reversal (46,XX disorder of sex development), sometimes progressing to squamous cell carcinoma of the skin. The gene shows low constraint against loss-of-function variants (pLI near 0), consistent with the recessive inheritance pattern.

OMIMResearchSummary from RefSeq, OMIM, UniProt
ARLOEUF 1.402 OMIM phenotypes
Clinical Summary— RSPO1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
11 unique Pathogenic / Likely Pathogenic· 54 VUS of 104 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
1.40LOEUF
pLI 0.000
Z-score 0.56
OE 0.83 (0.51–1.40)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
0.65Z-score
OE missense 0.86 (0.74–0.99)
138 obs / 161.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.83 (0.51–1.40)
0≤0.351.4
Missense OE0.86 (0.74–0.99)
0≤0.61.4
Synonymous OE1.07
0≤1.21.6
LoF obs/exp: 10 / 12.1Missense obs/exp: 138 / 161.1Syn Z: -0.47

ClinVar Variant Classifications

104 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9
Likely Pathogenic2
VUS54
Likely Benign21
Benign14
Conflicting2
9
Pathogenic
2
Likely Pathogenic
54
VUS
21
Likely Benign
14
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
5
0
4
0
9
Likely Pathogenic
1
0
1
0
2
VUS
1
46
5
2
54
Likely Benign
0
2
2
17
21
Benign
0
3
11
0
14
Conflicting
—2
Total7512319102

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

View in ClinVar →

Protein Context — Lollipop Plot

RSPO1 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Human RSPO1 Mutation Represses Beige Adipocyte Thermogenesis and Contributes to Diet-Induced Adiposity.
Sun Y et al.·Adv Sci (Weinh)
2023
R-spondin family biology and emerging linkages to cancer.
He Z et al.·Ann Med
2023Review
RSPO1-mutated keratinocytes from palmoplantar keratoderma display impaired differentiation, alteration of cell-cell adhesion, EMT-like phenotype and invasiveness properties: implications for squamous cell carcinoma susceptibility in patients with 46XX disorder of sexual development.
Dellambra E et al.·Orphanet J Rare Dis
2022Cohort
Dissecting the functional differences and clinical features of R-spondin family members in metastatic prostate cancer.
Deacon A et al.·Oncotarget
2025Functional
[Genetics of complex and syndromic palmoplantar keratoderma].
Sperelakis-Beedham B et al.·Ann Biol Clin (Paris)
2021Review
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Exploring the Involvement of RSPO1 Gene Variations in 46,XX DSD Patients With Mullerian Agenesis and/or Gonadal Dysgenesis-An Indian Study.
T S R et al.·J Obstet Gynaecol Res
2026Cohort
Deletion of Rspo1 or Rspo3 in the mesenchyme does not affect Wolffian duct maintenance or morphogenesis.
Jia S et al.·MicroPubl Biol
2026Open Access
Identification of a novel RSPO1-NUMT insertion in a LUAD patient cohort and the challenges and insights into NUMT detection highlighting the importance of reference genomes and population databases.
Tietzova I et al.·Transl Lung Cancer Res
2025Open AccessCohort
Enhancing Long-Term Survival and Self-Renewal of Primary Hepatocytes via Rapid Spheroid Formation Using Rocker System through Co-Culturing with HUVEC Over-Expressing RSPO1.
He Y et al.·Tissue Eng Regen Med
2025
Ontogeny of RSPO1, FOXL2, and RUNX1 during ovarian differentiation in the marsupial tammar wallaby.
Paranjpe MR et al.·Dev Dyn
2026Open Access
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients