RSPO1

Chr 1AR

R-spondin 1

Also known as: CRISTIN3, RSPO

NCBI Gene: 284654ENSG00000169218UniProt: Q2MKA7

This gene encodes a secreted activator protein with two cysteine-rich, furin-like domains and one thrombospondin type 1 domain. The encoded protein is a ligand for leucine-rich repeat-containing G-protein coupled receptors (LGR proteins) and positively regulates the Wnt signaling pathway. In mice, the protein induces the rapid onset of crypt cell proliferation and increases intestinal epithelial healing, providing a protective effect against chemotherapy-induced adverse effects. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2014]

Primary Disease Associations & Inheritance

Palmoplantar hyperkeratosis and true hermaphroditismMIM #610644
AR
Palmoplantar hyperkeratosis with squamous cell carcinoma of skin and sex reversalMIM #610644
AR
UniProtKeratoderma, palmoplantar, with squamous cell carcinoma of skin and sex reversal
104
ClinVar variants
11
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— RSPO1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
11 Pathogenic / Likely Pathogenic· 54 VUS of 104 total submissions

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.
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?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.
0.65Z-score
OE missense 0.86 (0.74–0.99)
138 obs / 161.1 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.0.83 (0.51–1.40)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.86 (0.74–0.99)
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.1.07
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
3
0
6
0
9
Likely Pathogenic
1
0
1
0
2
VUS
1
46
5
2
54
Likely Benign
0
2
2
17
21
Benign
0
2
12
0
14
Conflicting
—2
Total5502619102

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.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
R-SPONDIN 1; RSPO1
MIM #609595 · *

Palmoplantar hyperkeratosis and true hermaphroditism

MIM #610644

Molecular basis of disorder known

Autosomal recessive

Palmoplantar hyperkeratosis with squamous cell carcinoma of skin and sex reversal

MIM #610644

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
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
Novel RSPO1 mutation causing 46,XX testicular disorder of sex development with palmoplantar keratoderma: A review of literature and expansion of clinical phenotype.
Tallapaka K et al.·Am J Med Genet A
2018Review
Diagnosis and management of non-CAH 46,XX disorders/differences in sex development.
Yavas Abalı Z et al.·Front Endocrinol (Lausanne)
2024Review
R-spondin family biology and emerging linkages to cancer.
He Z et al.·Ann Med
2023Review
Rspo1 inhibited apoptosis of glucocorticoid-induced osteoblasts via Wnt/β-catenin pathway in Legg-Calve-Perthes disease.
Zhang T et al.·Adv Clin Exp Med
2023
The association of radiographic progression with serum R-spondin 1 (RSPO1) levels or Dickkopf-1 (DKK1)/RSPO1 ratios in rheumatoid arthritis patients: clinical evidence for reciprocal inhibition between DKK1 and RSPO1.
Choi BY et al.·Scand J Rheumatol
2014Cohort
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
The role of R-spondin proteins in cancer biology.
Ter Steege EJ et al.·Oncogene
2021Review
Genes promoting and disturbing testis development.
Barrionuevo FJ et al.·Histol Histopathol
2012Review
Goat RSPO1 over-expression rescues sex-reversal in Rspo1-knockout XX mice but does not perturb testis differentiation in XY or sex-reversed XX mice.
Buscara L et al.·Transgenic Res
2009
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
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
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
2025🔓 Open 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
2025
RSPO1, a potent inducer of pancreatic β cell neogenesis.
Silvano S et al.·Cell Rep Med
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools