RIPPLY2

Chr 6AR

ripply transcriptional repressor 2

Also known as: C6orf159, SCDO6, dJ237I15.1

NCBI Gene: 134701ENSG00000203877UniProt: Q5TAB7

This gene encodes a nuclear protein that belongs to a novel family of proteins required for vertebrate somitogenesis. Members of this family have a tetrapeptide WRPW motif that is required for interaction with the transcriptional repressor Groucho and a carboxy-terminal Ripply homology domain/Bowline-DSCR-Ledgerline conserved region required for transcriptional repression. Null mutant mice die soon after birth and display defects in axial skeleton segmentation due to defective somitogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

Primary Disease Associations & Inheritance

Spondylocostal dysostosis 6MIM #616566
AR
138
ClinVar variants
14
Pathogenic / LP
0.01
pLI score
0
Active trials
Clinical Summary— RIPPLY2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
14 Pathogenic / Likely Pathogenic· 76 VUS of 138 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.
1.26LOEUF
pLI 0.009
Z-score 1.11
OE 0.55 (0.27–1.26)
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.
-0.56Z-score
OE missense 1.19 (0.99–1.43)
82 obs / 69.0 exp
Tolerant

Tolerant to missense variation

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.0.55 (0.27–1.26)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.19 (0.99–1.43)
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.0.77
0≤1.21.6
LoF obs/exp: 4 / 7.2Missense obs/exp: 82 / 69.0Syn Z: 0.94

ClinVar Variant Classifications

138 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13
Likely Pathogenic1
VUS76
Likely Benign36
Benign9
Conflicting3
13
Pathogenic
1
Likely Pathogenic
76
VUS
36
Likely Benign
9
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
13
0
13
Likely Pathogenic
1
0
0
0
1
VUS
7
46
22
1
76
Likely Benign
0
2
16
18
36
Benign
0
0
6
3
9
Conflicting
—3
Total8485722138

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

View in ClinVar →

Protein Context — Lollipop Plot

RIPPLY2 · 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

Spondylocostal dysostosis 6

MIM #616566

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — RIPPLY2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Incomplete spinal cord injury following minor trauma in two siblings with spondylocostal dysostis type 6.
van der Vlis TAMB et al.·Spine Deform
2024
Congenital posterior cervical spine malformation due to biallelic c.240-4T>G RIPPLY2 variant: A discrete entity.
Serey-Gaut M et al.·Am J Med Genet A
2020Case report
Congenital cervical spine malformation due to bi-allelic RIPPLY2 variants in spondylocostal dysostosis type 6.
Wegler M et al.·Clin Genet
2021Case report
Identification of bi-allelic LFNG variants in three patients and further clinical and molecular refinement of spondylocostal dysostosis 3.
Lecca M et al.·Clin Genet
2023Cohort
[Clinical Characteristics and Genetic Analysis of Klippel-Feil Syndrome].
Li ZQ et al.·Zhongguo Yi Xue Ke Xue Yuan Xue Bao
2021
The mutational burden and oligogenic inheritance in Klippel-Feil syndrome.
Li Z et al.·BMC Musculoskelet Disord
2020
Association of FCGR2A/FCGR3A variant rs2099684 with Takayasu arteritis in the Han Chinese population.
Chen S et al.·Oncotarget
2017
A Confirmatory Case of Severe Spondylocostal Dysostosis Caused by Biallelic Loss-of-Function of DMRT2.
Rips J et al.·Am J Med Genet A
2026Case report
Genetic insights into the 'sandwich fusion' subtype of Klippel-Feil syndrome: novel FGFR2 mutations identified by 21 cases of whole-exome sequencing.
Xu N et al.·Orphanet J Rare Dis
2024Cohort
Homozygous DMRT2 variant associates with severe rib malformations in a newborn.
Bouman A et al.·Am J Med Genet A
2018Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

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External Resources

Links to major genomics databases and tools