RSPO2

Chr 8

R-spondin 2

Also known as: CRISTIN2, HHRRD, TETAMS2

NCBI Gene: 340419 ENSG00000147655 UniProt: Q6UXX9

The protein is a secreted ligand that activates canonical Wnt signaling by binding to LGR4-6 receptors and plays a crucial role in embryonic limb specification. Autosomal recessive mutations cause tetraamelia syndrome 2 (absence of all four limbs) and humerofemoral hypoplasia with radiotibial ray deficiency, representing severe limb malformation disorders. The gene shows tolerance to loss-of-function variants in the general population (low pLI), consistent with its recessive inheritance pattern.

ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the R-spondin family of proteins. These proteins are secreted ligands of leucine-rich repeat containing G protein-coupled receptors that enhance Wnt signaling through the inhibition of ubiquitin E3 ligases. A chromosomal translocation including this locus that results in the formation of a gene fusion has been identified in multiple human cancers. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.76

Clinical Summary— RSPO2

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Population Constraint (gnomAD)

Low constraint (pLI 0.02) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

5 unique Pathogenic / Likely Pathogenic· 53 VUS of 109 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?

0.76LOEUF

pLI 0.025

Z-score 2.19

OE 0.36 (0.19–0.76)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.50Z-score

OE missense 0.88 (0.76–1.02)

121 obs / 137.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.36 (0.19–0.76)

0≤0.351.4

Missense OE?0.88 (0.76–1.02)

0≤0.61.4

Synonymous OE?1.24

0≤1.21.6

LoF obs/exp: 5 / 13.8Missense obs/exp: 121 / 137.4Syn Z: -1.26

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongRSPO2-related tetraamelia with lung agenesisLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6744th %ile

GOF

0.5465th %ile

LOF

0.3550th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

109 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic2

VUS53

Likely Benign39

Benign9

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	1	0	0	3
Likely Pathogenic	2	0	0	0	2
VUS	1	51	1	0	53
Likely Benign	0	1	9	29	39
Benign	0	1	6	2	9
Total	5	54	16	31	106

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

View in ClinVar →

38 pathogenic / likely-pathogenic (of 43) ClinVar copy-number / structural variants overlap RSPO2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →