RSPO1

Chr 1

R-spondin 1

Also known as: CRISTIN3, RSPO

NCBI Gene: 284654 ENSG00000169218 UniProt: Q2MKA7

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.

ResearchSummary from RefSeq, OMIM, UniProt

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]

ResearchGenerating clinical summary…

LOEUF 1.40

Clinical Summary— RSPO1

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

6 unique Pathogenic / Likely Pathogenic· 49 VUS of 93 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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 OE?0.83 (0.51–1.40)

0≤0.351.4

Missense OE?0.86 (0.74–0.99)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 10 / 12.1Missense obs/exp: 138 / 161.1Syn Z: -0.47

ClinVar Variant Classifications

93 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic1

VUS49

Likely Benign20

Benign14

Conflicting2

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	5	0	0	0	5
Likely Pathogenic	1	0	0	0	1
VUS	1	46	0	2	49
Likely Benign	0	2	1	17	20
Benign	0	3	11	0	14
Conflicting	—				2
Total	7	51	12	19	91

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

View in ClinVar →

5 pathogenic / likely-pathogenic (of 12) ClinVar copy-number / structural variants overlap RSPO1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →