RIPPLY2

Summary

RIPPLY2 (ripply transcriptional repressor 2, HGNC:21390) is a protein-coding gene on chromosome 6q14.2, encoding Protein ripply2 (Q5TAB7). Plays a role in somitogenesis.

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.

Source: NCBI Gene 134701 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spondylocostal dysostosis 6, autosomal recessive (Strong, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 103 total — 1 likely-pathogenic
• Phenotypes (HPO): 43
• MANE Select transcript: NM_001009994

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21390
Approved symbol	RIPPLY2
Name	ripply transcriptional repressor 2
Location	6q14.2
Locus type	gene with protein product
Status	Approved
Aliases	dJ237I15.1
Ensembl gene	ENSG00000203877
Ensembl biotype	protein_coding
OMIM	609891
Entrez	134701

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 retained_intron

ENST00000369687, ENST00000369689, ENST00000635617

RefSeq mRNA: 3 — MANE Select: NM_001009994 NM_001009994, NM_001400899, NM_001400900

CCDS: CCDS34493

Canonical transcript exons

ENST00000369689 — 4 exons

Exon	Start	End
ENSE00001450639	83857242	83857515
ENSE00001450641	83853695	83853773
ENSE00001450642	83853360	83853511
ENSE00003755044	83854097	83854161

Expression profiles

Bgee: expression breadth ubiquitous, 146 present calls, max score 89.99.

FANTOM5 (CAGE): breadth broad, TPM avg 1.2954 / max 67.0052, expressed in 216 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
68780	1.2329	210
204087	0.0625	44

Top tissues by expression

239 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
cerebellar hemisphere	UBERON:0002245	89.99	gold quality
cerebellar cortex	UBERON:0002129	89.85	gold quality
right hemisphere of cerebellum	UBERON:0014890	89.78	gold quality
Brodmann (1909) area 9	UBERON:0013540	89.53	gold quality
cerebellum	UBERON:0002037	88.86	gold quality
prefrontal cortex	UBERON:0000451	87.78	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.61	gold quality
nucleus accumbens	UBERON:0001882	86.26	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	86.22	gold quality
anterior cingulate cortex	UBERON:0009835	86.10	gold quality
right frontal lobe	UBERON:0002810	85.51	gold quality
putamen	UBERON:0001874	85.13	gold quality
caudate nucleus	UBERON:0001873	84.52	gold quality
hypothalamus	UBERON:0001898	84.10	gold quality
frontal cortex	UBERON:0001870	84.01	gold quality
neocortex	UBERON:0001950	83.49	gold quality
amygdala	UBERON:0001876	82.80	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	82.41	gold quality
cerebral cortex	UBERON:0000956	82.30	gold quality
brain	UBERON:0000955	82.24	gold quality
forebrain	UBERON:0001890	82.02	gold quality
spinal cord	UBERON:0002240	80.43	gold quality
adenohypophysis	UBERON:0002196	80.16	gold quality
Ammon’s horn	UBERON:0001954	79.96	gold quality
pituitary gland	UBERON:0000007	79.86	gold quality
substantia nigra	UBERON:0002038	79.80	gold quality
cortical plate	UBERON:0005343	79.48	gold quality
midbrain	UBERON:0001891	77.61	gold quality
temporal lobe	UBERON:0001871	77.28	gold quality
islet of Langerhans	UBERON:0000006	75.73	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.94

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MESP2

miRNA regulators (miRDB)

12 targeting RIPPLY2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-6771-3P	98.20	66.53	971
HSA-MIR-3201	97.16	65.42	1044

Literature-anchored findings (GeneRIF, showing 4)

• Compares Ripply proteins in zebrafish, mouse, human, and amphioxus. (PMID:16326386)
• Functional analysis of the mouse Ripply2 ortholog. (PMID:17531978)
• Congenital posterior cervical spine malformation due to biallelic c.240-4T>G RIPPLY2 variant: A discrete entity. (PMID:32212228)
• Congenital cervical spine malformation due to bi-allelic RIPPLY2 variants in spondylocostal dysostosis type 6. (PMID:33410135)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ripply1	ENSDARG00000054103
mus_musculus	Ripply2	ENSMUSG00000047897
rattus_norvegicus	Ripply2	ENSRNOG00000010004

Paralogs (2): RIPPLY1 (ENSG00000147223), RIPPLY3 (ENSG00000183145)

Protein

Protein identifiers

Protein ripply2 — Q5TAB7 (reviewed: Q5TAB7)

All UniProt accessions (1): Q5TAB7

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in somitogenesis. Required for somite segregation and establishment of rostrocaudal polarity in somites.

Subcellular location. Nucleus.

Disease relevance. Spondylocostal dysostosis 6, autosomal recessive (SCDO6) [MIM:616566] A form of spondylocostal dysostosis, a condition of variable severity associated with vertebral and rib segmentation defects. The main skeletal malformations include fusion of vertebrae, hemivertebrae, fusion of certain ribs, and other rib malformations. Deformity of the chest and spine (severe scoliosis, kyphoscoliosis and lordosis) is a natural consequence of the malformation and leads to a dwarf-like appearance. As the thorax is small, infants frequently have respiratory insufficiency and repeated respiratory infections resulting in life-threatening complications in the first year of life. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The ripply homology domain is required for transcriptional repression. The WRPW motif is required for binding to tle/groucho proteins.

Similarity. Belongs to the ripply family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q5TAB7-1	1	yes
Q5TAB7-2	2

RefSeq proteins (3): NP_001009994, NP_001387828, NP_001387829 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR028127	Ripply_fam	Family

Pfam: PF14998

UniProt features (6 total): region of interest 2, chain 1, short sequence motif 1, compositionally biased region 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5TAB7-F1	62.67	0.07

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9824272	Somitogenesis

MSigDB gene sets: 146 (showing top): GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_AXIS_SPECIFICATION, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_EMBRYONIC_AXIS_SPECIFICATION, GOBP_SPECIFICATION_OF_SYMMETRY, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_BONE_DEVELOPMENT, GOBP_ANTERIOR_POSTERIOR_PATTERN_SPECIFICATION, GOBP_EMBRYONIC_PATTERN_SPECIFICATION, GOBP_SOMITOGENESIS, GOBP_SEGMENTATION, GOBP_OSSIFICATION, GOBP_ANTERIOR_POSTERIOR_AXIS_SPECIFICATION

GO Biological Process (11): negative regulation of transcription by RNA polymerase II (GO:0000122), ossification (GO:0001503), somitogenesis (GO:0001756), Notch signaling pathway (GO:0007219), determination of left/right symmetry (GO:0007368), embryonic pattern specification (GO:0009880), somite rostral/caudal axis specification (GO:0032525), post-anal tail morphogenesis (GO:0036342), bone morphogenesis (GO:0060349), axis specification (GO:0009798), regulation of gene expression (GO:0010468)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (1): nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Formation of paraxial mesoderm	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
pattern specification process	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
multicellular organismal process	1
anterior/posterior pattern specification	1
segmentation	1
chordate embryonic development	1
anatomical structure formation involved in morphogenesis	1
somite development	1
cell surface receptor signaling pathway	1
determination of bilateral symmetry	1
left/right pattern formation	1
embryo development	1
embryonic axis specification	1
somitogenesis	1
anterior/posterior axis specification	1
anatomical structure morphogenesis	1
animal organ morphogenesis	1
skeletal system morphogenesis	1
bone development	1
gene expression	1
regulation of macromolecule biosynthetic process	1
binding	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

474 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RIPPLY2	MESP2	Q0VG99	807
RIPPLY2	TBX6	O95947	750
RIPPLY2	MSGN1	A6NI15	590
RIPPLY2	MEOX1	P50221	576
RIPPLY2	LFNG	Q8NES3	571
RIPPLY2	UNCX	A6NJT0	532
RIPPLY2	CYB5R4	Q7L1T6	479
RIPPLY2	TBX18	O95935	460
RIPPLY2	DLL3	Q9NYJ7	447
RIPPLY2	DLL1	O00548	425
RIPPLY2	CEP162	Q5TB80	413
RIPPLY2	SYNDIG1L	A6NDD5	411
RIPPLY2	MTCL3	Q5TF21	408
RIPPLY2	C6orf163	Q5TEZ5	398
RIPPLY2	PABIR3	Q6P4D5	395

IntAct

52 interactions, top by confidence:

A	B	Type	Score
RIPPLY2	KASH5	psi-mi:“MI:0915”(physical association)	0.790
KASH5	RIPPLY2	psi-mi:“MI:0915”(physical association)	0.790
PBX2	RIPPLY2	psi-mi:“MI:0915”(physical association)	0.630
RIPPLY2	PBX2	psi-mi:“MI:0915”(physical association)	0.630
TFG	RIPPLY2	psi-mi:“MI:0915”(physical association)	0.560
RIPPLY2	SYNE4	psi-mi:“MI:0915”(physical association)	0.560
RIPPLY2	TFG	psi-mi:“MI:0915”(physical association)	0.560
SYNE4	RIPPLY2	psi-mi:“MI:0915”(physical association)	0.560
RIPPLY2	PBX4	psi-mi:“MI:0915”(physical association)	0.560
AVPI1	RIPPLY2	psi-mi:“MI:0915”(physical association)	0.560
C3orf36	RIPPLY2	psi-mi:“MI:0915”(physical association)	0.560
NDUFB7	RIPPLY2	psi-mi:“MI:0915”(physical association)	0.560
RIPPLY2	GOLM1	psi-mi:“MI:0915”(physical association)	0.560
ELAVL4	RIPPLY2	psi-mi:“MI:0915”(physical association)	0.560
RIPPLY2	SPRED1	psi-mi:“MI:0915”(physical association)	0.560
HTT	RIPPLY2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (30): RIPPLY2 (Two-hybrid), CCDC155 (Two-hybrid), SYNE4 (Two-hybrid), TLE4 (Affinity Capture-MS), TLE2 (Affinity Capture-MS), AES (Affinity Capture-MS), TLE3 (Affinity Capture-MS), TLE1 (Affinity Capture-MS), TRIP6 (Affinity Capture-MS), USP4 (Affinity Capture-MS), RBM23 (Affinity Capture-MS), FERMT2 (Affinity Capture-MS), EXOG (Affinity Capture-MS), CCDC155 (Two-hybrid), RIPPLY2 (Two-hybrid)

ESM2 similar proteins: B1H3B4, B7XDF1, D3ZDX9, D6RGH6, F1SLM8, G3N1S4, O35144, P07516, P18302, P57055, Q0D2K3, Q0II70, Q0X0E2, Q14684, Q14DQ1, Q15554, Q2KI80, Q2WG76, Q2WG78, Q3TVI4, Q3U0L2, Q3UZ45, Q4KLY2, Q5FVJ4, Q5R8C5, Q5RA50, Q5T7N3, Q5TAB7, Q5XKK7, Q60829, Q6J4I0, Q6PJ61, Q7TNF9, Q86V42, Q8BFW3, Q8BRJ3, Q8C4S8, Q8IWP9, Q8NC24, Q8NE31

Diamond homologs: B1H3B4, B7XDF1, P57055, Q0D2K3, Q25QX6, Q2WG76, Q2WG77, Q2WG78, Q2WG79, Q2WG80, Q5I2D0, Q5TAB7, Q8QGU6, Q924S9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

103 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	57
Likely benign	36
Benign	8

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
218314	NM_001009994.3(RIPPLY2):c.299del (p.Leu100fs)	Likely pathogenic

SpliceAI

724 predictions. Top by Δscore:

Variant	Effect	Δscore
6:83853980:GCTGC:G	donor_gain	1.0000
6:83853509:CGGGT:C	donor_loss	0.9900
6:83853510:GG:G	donor_gain	0.9900
6:83853510:GGGT:G	donor_loss	0.9900
6:83853511:GG:G	donor_gain	0.9900
6:83853511:GGT:G	donor_loss	0.9900
6:83853512:G:GA	donor_loss	0.9900
6:83853512:G:GG	donor_gain	0.9900
6:83853513:TAGGC:T	donor_loss	0.9900
6:83853770:GGCG:G	donor_gain	0.9900
6:83853771:GCG:G	donor_gain	0.9900
6:83853771:GCGG:G	donor_gain	0.9900
6:83853774:G:GG	donor_gain	0.9900
6:83853972:G:GT	donor_gain	0.9900
6:83854091:CTCCA:C	acceptor_loss	0.9900
6:83854092:TCCAG:T	acceptor_loss	0.9900
6:83854093:CCAG:C	acceptor_loss	0.9900
6:83854094:CA:C	acceptor_loss	0.9900
6:83854095:A:AG	acceptor_gain	0.9900
6:83854095:A:G	acceptor_loss	0.9900
6:83854096:G:A	acceptor_loss	0.9900
6:83854096:G:GG	acceptor_gain	0.9900
6:83854132:A:T	donor_gain	0.9900
6:83854157:GTCAG:G	donor_gain	0.9900
6:83854159:CAG:C	donor_loss	0.9900
6:83854160:AGGTG:A	donor_loss	0.9900
6:83854161:GG:G	donor_loss	0.9900
6:83854162:GT:G	donor_loss	0.9900
6:83854163:TGAG:T	donor_loss	0.9900
6:83854839:G:GT	donor_gain	0.9900

AlphaMissense

828 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:83857328:T:A	I109N	0.997
6:83857328:T:C	I109T	0.996
6:83857328:T:G	I109S	0.996
6:83857301:T:C	L100P	0.994
6:83857249:T:A	W83R	0.991
6:83857249:T:C	W83R	0.991
6:83857251:G:C	W83C	0.991
6:83857251:G:T	W83C	0.991
6:83854158:T:A	V79D	0.990
6:83857321:G:C	A107P	0.990
6:83857322:C:A	A107D	0.989
6:83857298:T:C	L99P	0.987
6:83857310:T:C	F103S	0.987
6:83854153:C:A	H77Q	0.985
6:83854153:C:G	H77Q	0.985
6:83857244:T:C	L81P	0.985
6:83853713:A:C	R38S	0.984
6:83853713:A:T	R38S	0.984
6:83854151:C:G	H77D	0.984
6:83857320:A:C	Q106H	0.984
6:83857320:A:T	Q106H	0.984
6:83857277:T:C	L92S	0.983
6:83857301:T:A	L100Q	0.983
6:83857330:T:C	S110P	0.983
6:83854152:A:G	H77R	0.982
6:83857288:G:C	A96P	0.982
6:83857279:T:G	Y93D	0.979
6:83857250:G:C	W83S	0.978
6:83853717:T:A	W40R	0.977
6:83853717:T:C	W40R	0.977

dbSNP variants (sampled 300 via entrez): RS1000510704 (6:83855215 C>A,G,T), RS1000870904 (6:83852271 G>A), RS1002119759 (6:83854912 T>C), RS1002334331 (6:83855040 C>G), RS1002592659 (6:83853278 G>A), RS1002667414 (6:83854559 A>T), RS1002843085 (6:83854607 A>G), RS1003310971 (6:83856307 A>C), RS1003794154 (6:83856891 G>A,T), RS1003990488 (6:83856054 T>TA), RS1004063959 (6:83856347 C>G,T), RS1005795896 (6:83856246 T>A), RS1006071990 (6:83853259 T>G), RS1006243106 (6:83856589 T>C), RS1006542329 (6:83857945 C>A)

Disease associations

OMIM: gene MIM:609891 | disease phenotypes: MIM:616566, MIM:214300

GenCC curated gene-disease

Disease	Classification	Inheritance
spondylocostal dysostosis 6, autosomal recessive	Strong	Autosomal recessive
autosomal recessive spondylocostal dysostosis	Supportive	Autosomal recessive

Mondo (3): spondylocostal dysostosis 6, autosomal recessive (MONDO:0014694), Klippel-Feil syndrome 2, autosomal recessive (MONDO:0008958), autosomal recessive spondylocostal dysostosis (MONDO:0010180)

Orphanet (2): Autosomal recessive spondylocostal dysostosis (Orphanet:2311), Isolated Klippel-Feil syndrome (Orphanet:2345)

HPO phenotypes

43 total (30 of 43 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000008	Abnormal morphology of female internal genitalia
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000069	Abnormality of the ureter
HP:0000175	Cleft palate
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000269	Prominent occiput
HP:0000337	Broad forehead
HP:0000343	Long philtrum
HP:0000358	Posteriorly rotated ears
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000772	Abnormal rib morphology
HP:0000776	Congenital diaphragmatic hernia
HP:0000902	Rib fusion
HP:0001249	Intellectual disability
HP:0001511	Intrauterine growth retardation
HP:0001537	Umbilical hernia
HP:0002093	Respiratory insufficiency
HP:0002435	Meningocele
HP:0002650	Scoliosis
HP:0002808	Kyphosis
HP:0002937	Hemivertebrae
HP:0002947	Cervical kyphosis
HP:0003298	Spina bifida occulta
HP:0003312	Abnormal form of the vertebral bodies
HP:0003316	Butterfly vertebrae

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C536888	Klippel Feil syndrome recessive type (supp.)
C535781	Spondylocostal dysostosis, autosomal recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

11 total (human), top 11 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
N(4)-hydroxycytidine	decreases expression	1
decabromobiphenyl ether	affects expression	1
arsenite	increases methylation	1
butyraldehyde	increases expression	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	decreases expression	1
Acetaminophen	increases expression	1
Benzo(a)pyrene	increases methylation	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Cadmium Chloride	decreases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.