RIPPLY3

Summary

RIPPLY3 (ripply transcriptional repressor 3, HGNC:3047) is a protein-coding gene on chromosome 21q22.13, encoding Protein ripply3 (P57055). Acts as a transcriptional corepressor.

Predicted to be involved in embryonic pattern specification and negative regulation of transcription by RNA polymerase II. Predicted to act upstream of or within negative regulation of cell population proliferation. Predicted to be active in nucleus.

Source: NCBI Gene 53820 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 32 total
• MANE Select transcript: NM_018962

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3047
Approved symbol	RIPPLY3
Name	ripply transcriptional repressor 3
Location	21q22.13
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000183145
Ensembl biotype	protein_coding
OMIM	609892
Entrez	53820

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding_CDS_not_defined, 1 protein_coding

ENST00000329553, ENST00000485272, ENST00000490393

RefSeq mRNA: 3 — MANE Select: NM_018962 NM_001317768, NM_001317777, NM_018962

CCDS: CCDS13648

Canonical transcript exons

ENST00000329553 — 4 exons

Exon	Start	End
ENSE00001292766	37006702	37006876
ENSE00003500060	37017874	37019662
ENSE00003508393	37013551	37013618
ENSE00003623418	37008157	37008223

Expression profiles

Bgee: expression breadth broad, 66 present calls, max score 81.14.

FANTOM5 (CAGE): breadth broad, TPM avg 1.3113 / max 80.6520, expressed in 349 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
189012	1.3113	349

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	81.14	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.53	gold quality
cardiac muscle of right atrium	UBERON:0003379	63.13	gold quality
left ventricle myocardium	UBERON:0006566	62.50	gold quality
corpus epididymis	UBERON:0004359	61.65	gold quality
diaphragm	UBERON:0001103	61.22	gold quality
lower lobe of lung	UBERON:0008949	59.42	silver quality
cauda epididymis	UBERON:0004360	58.97	silver quality
islet of Langerhans	UBERON:0000006	58.62	gold quality
pigmented layer of retina	UBERON:0001782	58.24	silver quality
caput epididymis	UBERON:0004358	57.36	gold quality
hair follicle	UBERON:0002073	57.26	gold quality
pancreatic ductal cell	CL:0002079	56.81	silver quality
myocardium	UBERON:0002349	56.81	gold quality
skin of hip	UBERON:0001554	56.77	gold quality
decidua	UBERON:0002450	56.55	gold quality
stromal cell of endometrium	CL:0002255	54.82	silver quality
right lung	UBERON:0002167	54.65	gold quality
oviduct epithelium	UBERON:0004804	50.86	gold quality
epithelial cell of pancreas	CL:0000083	50.64	gold quality
quadriceps femoris	UBERON:0001377	50.42	gold quality
vastus lateralis	UBERON:0001379	50.05	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.83	gold quality
ventricular zone	UBERON:0003053	49.64	gold quality
deltoid	UBERON:0001476	49.53	gold quality
tibialis anterior	UBERON:0001385	49.50	silver quality
endometrium	UBERON:0001295	49.49	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
cortex of kidney	UBERON:0001225	49.22	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.26

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

57 targeting RIPPLY3, 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-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548N	99.98	71.94	4170
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-4255	99.72	67.70	1541
HSA-MIR-12129	99.72	67.45	1311
HSA-MIR-4465	99.71	72.56	2096
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311

Literature-anchored findings (GeneRIF, showing 1)

• deleterious variants in RIPPLY3 are potential molecular mechanisms involved in the pathogenesis of human Conotruncal heart defect. (PMID:30241482)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ripply3	ENSDARG00000036974
mus_musculus	Ripply3	ENSMUSG00000022941
rattus_norvegicus	Ripply3	ENSRNOG00000001684

Paralogs (2): RIPPLY1 (ENSG00000147223), RIPPLY2 (ENSG00000203877)

Protein

Protein identifiers

Protein ripply3 — P57055 (reviewed: P57055)

Alternative names: Down syndrome critical region protein 6

All UniProt accessions (1): P57055

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a transcriptional corepressor. Negative regulator of the transcriptional activity of TBX1. Plays a role in the development of the pharyngeal apparatus and derivatives.

Subunit / interactions. Interacts with TBX1.

Subcellular location. Nucleus.

Tissue specificity. Expressed at a low level in fetal kidney and fetal brain.

Domain organisation. The Ripply homology domain and the WRPW motif are both necessary for its transcriptional corepressor activity on the transcription activator TBX1. The WRPW motif is required for binding to tle/groucho proteins.

Similarity. Belongs to the ripply family.

Isoforms (2)

UniProt ID	Names	Canonical?
P57055-1	1, A	yes
P57055-2	2, B, C, D

RefSeq proteins (1): NP_061835* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR028127	Ripply_fam	Family

Pfam: PF14998

UniProt features (9 total): region of interest 3, compositionally biased region 3, chain 1, short sequence motif 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P57055-F1	61.64	0.08

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 87 (showing top): GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, LEE_NEURAL_CREST_STEM_CELL_DN, GOZGIT_ESR1_TARGETS_DN, WEI_MYCN_TARGETS_WITH_E_BOX, MARTORIATI_MDM4_TARGETS_NEUROEPITHELIUM_DN, GOBP_EMBRYONIC_PATTERN_SPECIFICATION, BILD_E2F3_ONCOGENIC_SIGNATURE, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_UP, CHO_NR4A1_TARGETS, GOBP_PHARYNGEAL_SYSTEM_DEVELOPMENT, GOBP_EMBRYO_DEVELOPMENT, chr21q22, DANG_BOUND_BY_MYC, GOBP_CIRCULATORY_SYSTEM_DEVELOPMENT, NUYTTEN_EZH2_TARGETS_DN

GO Biological Process (6): negative regulation of transcription by RNA polymerase II (GO:0000122), heart development (GO:0007507), cell population proliferation (GO:0008283), negative regulation of cell population proliferation (GO:0008285), embryonic pattern specification (GO:0009880), pharyngeal system development (GO:0060037)

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

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
animal organ development	1
circulatory system development	1
cellular process	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
pattern specification process	1
embryo development	1
chordate embryonic development	1
system development	1
binding	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

366 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RIPPLY3	IQANK1	A8MXQ7	529
RIPPLY3	INSM1	Q01101	511
RIPPLY3	NEUROG3	Q9Y4Z2	453
RIPPLY3	PIGP	P57054	447
RIPPLY3	HMG20A	Q9NP66	445
RIPPLY3	PPY	P01298	427
RIPPLY3	ARX	Q96QS3	424
RIPPLY3	FAM237B	A0A1B0GVD1	419
RIPPLY3	INSM2	Q96T92	414
RIPPLY3	SH3BGR	P55822	413
RIPPLY3	PSMG1	O95456	370
RIPPLY3	RACK1	P25388	367
RIPPLY3	PAX9	P55771	365
RIPPLY3	REST	Q13127	357
RIPPLY3	SH3BGRL	O75368	352

IntAct

44 interactions, top by confidence:

A	B	Type	Score
RIPPLY3	TIFA	psi-mi:“MI:0915”(physical association)	0.670
RIPPLY3	MCRS1	psi-mi:“MI:0915”(physical association)	0.670
RIPPLY3	TBX1	psi-mi:“MI:0915”(physical association)	0.560
RIPPLY3	TRAF2	psi-mi:“MI:0915”(physical association)	0.560
RIPPLY3	CEP76	psi-mi:“MI:0915”(physical association)	0.560
RIPPLY3	ORC2	psi-mi:“MI:0915”(physical association)	0.560
RIPPLY3	INCA1	psi-mi:“MI:0915”(physical association)	0.560
PSMB1	RIPPLY3	psi-mi:“MI:0915”(physical association)	0.560
RIPPLY3	A2ML1	psi-mi:“MI:0914”(association)	0.350
TLE1	TBX1	psi-mi:“MI:0914”(association)	0.350
RINL	SERPINB8	psi-mi:“MI:0914”(association)	0.350
TLE4	RIPPLY3	psi-mi:“MI:0914”(association)	0.350
RIPPLY3	TIFA	psi-mi:“MI:0915”(physical association)	0.000
RIPPLY3	CEP76	psi-mi:“MI:0915”(physical association)	0.000
RIPPLY3	ORC2	psi-mi:“MI:0915”(physical association)	0.000
RIPPLY3	TRAF2	psi-mi:“MI:0915”(physical association)	0.000
RIPPLY3	INCA1	psi-mi:“MI:0915”(physical association)	0.000
RIPPLY3	MCRS1	psi-mi:“MI:0915”(physical association)	0.000
PSMB1	RIPPLY3	psi-mi:“MI:0915”(physical association)	0.000
RIPPLY3	PIP4P2	psi-mi:“MI:0915”(physical association)	0.000
RIPPLY3	RHOBTB3	psi-mi:“MI:0915”(physical association)	0.000
RIPPLY3	SNRNP70	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (114): RIPPLY3 (Two-hybrid), RIPPLY3 (Two-hybrid), RIPPLY3 (Two-hybrid), RIPPLY3 (Two-hybrid), RIPPLY3 (Two-hybrid), MCRS1 (Two-hybrid), INCA1 (Two-hybrid), RIPPLY3 (Proximity Label-MS), C17orf70 (Affinity Capture-MS), S100A7A (Affinity Capture-MS), IMPA2 (Affinity Capture-MS), SQRDL (Affinity Capture-MS), ORM1 (Affinity Capture-MS), IGHG2 (Affinity Capture-MS), A2ML1 (Affinity Capture-MS)

ESM2 similar proteins: A0JNJ4, A2APT9, A6NEL2, A6NJG2, O00221, O54910, O70146, O73895, O94761, O94989, P57055, P98077, Q0VCS0, Q15569, Q17QH7, Q2M3G4, Q2M3V2, Q3UYR4, Q494U1, Q4KLY2, Q5F267, Q5R866, Q5RA67, Q5TGS1, Q5VTJ3, Q63572, Q6PAJ3, Q6PB97, Q6PCT2, Q6PJ61, Q6ZMQ8, Q6ZVH7, Q7TSX9, Q7Z3H0, Q80SU3, Q80VJ8, Q80YE4, Q86SH2, Q8BG26, Q8BG80

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

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	26
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

745 predictions. Top by Δscore:

Variant	Effect	Δscore
21:37017873:GA:G	acceptor_gain	1.0000
21:37017866:A:G	acceptor_gain	0.9900
21:37017872:A:AG	acceptor_gain	0.9900
21:37017873:G:GG	acceptor_gain	0.9900
21:37017873:GAGT:G	acceptor_gain	0.9900
21:37018016:G:GT	donor_gain	0.9900
21:37007103:G:GT	donor_gain	0.9800
21:37007119:A:T	donor_gain	0.9800
21:37010026:G:T	donor_gain	0.9800
21:37017870:TTA:T	acceptor_loss	0.9800
21:37017872:A:T	acceptor_loss	0.9800
21:37006802:G:GT	donor_gain	0.9600
21:37007118:G:GT	donor_gain	0.9600
21:37017865:A:AG	acceptor_gain	0.9600
21:37017873:GAGTC:G	acceptor_gain	0.9600
21:37017868:T:G	acceptor_gain	0.9500
21:37017871:TAGAG:T	acceptor_gain	0.9500
21:37010071:G:GT	donor_gain	0.9400
21:37017870:TTAG:T	acceptor_gain	0.9400
21:37017870:TTAGA:T	acceptor_gain	0.9400
21:37017873:G:C	acceptor_gain	0.9400
21:37018049:G:GT	donor_gain	0.9400
21:37007017:C:T	donor_gain	0.9300
21:37007086:G:GT	donor_gain	0.9300
21:37007184:GCTCC:G	donor_gain	0.9300
21:37017872:AGAG:A	acceptor_gain	0.9300
21:37010158:ACCT:A	donor_gain	0.9200
21:37013549:A:AG	acceptor_gain	0.9200
21:37013550:G:GG	acceptor_gain	0.9200
21:37017869:A:AG	acceptor_gain	0.9200

AlphaMissense

1200 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:37013602:T:C	F75L	0.994
21:37013604:T:A	F75L	0.994
21:37013604:T:G	F75L	0.994
21:37017941:T:C	F103L	0.994
21:37017943:C:A	F103L	0.994
21:37017943:C:G	F103L	0.994
21:37017965:T:C	F111L	0.981
21:37017967:C:A	F111L	0.981
21:37017967:C:G	F111L	0.981
21:37017942:T:C	F103S	0.979
21:37013603:T:C	F75S	0.976
21:37008178:G:C	W42C	0.975
21:37008178:G:T	W42C	0.975
21:37013610:T:A	H77Q	0.975
21:37013610:T:G	H77Q	0.975
21:37017952:A:C	Q106H	0.975
21:37017952:A:T	Q106H	0.975
21:37017942:T:G	F103C	0.974
21:37017960:T:A	I109N	0.973
21:37008176:T:A	W42R	0.970
21:37008176:T:C	W42R	0.970
21:37017895:G:C	K87N	0.969
21:37017895:G:T	K87N	0.969
21:37008169:G:C	W39C	0.968
21:37008169:G:T	W39C	0.968
21:37017874:A:C	R80S	0.968
21:37017874:A:T	R80S	0.968
21:37017882:T:C	L83S	0.965
21:37013603:T:G	F75C	0.962
21:37013609:A:G	H77R	0.961

dbSNP variants (sampled 300 via entrez): RS1000014081 (21:37007504 G>A,T), RS1000084111 (21:37007058 C>T), RS1000136494 (21:37006854 C>G,T), RS1000360103 (21:37018287 C>T), RS1000374185 (21:37012212 T>A,C), RS1000685772 (21:37017389 C>T), RS1000915398 (21:37018011 C>T), RS1001050650 (21:37006402 G>A), RS1001204850 (21:37018655 G>GT), RS1001352767 (21:37012917 T>C), RS1001591461 (21:37006950 G>C,T), RS1001634867 (21:37018377 T>C), RS1002360201 (21:37011660 C>G), RS1002433668 (21:37011312 A>G), RS1002563147 (21:37006096 G>T)

Disease associations

OMIM: gene MIM:609892 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST008362_72	Birth weight	2.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004344	birth weight

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

36 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, increases methylation, affects expression, decreases expression	6
Benzo(a)pyrene	increases methylation, increases expression	4
Aflatoxin B1	affects expression, increases expression	3
Cisplatin	affects expression, increases expression	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
OTX015	decreases expression	1
mivebresib	decreases expression	1
bisphenol A	affects cotreatment, increases methylation	1
trichostatin A	increases expression	1
sodium arsenite	decreases expression	1
mercuric bromide	affects cotreatment, decreases expression	1
pentanal	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
NSC 689534	affects binding, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Decitabine	affects expression	1
Zoledronic Acid	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Copper	affects binding, decreases expression	1
Cyclophosphamide	increases expression	1
Dactinomycin	increases expression	1
Etoposide	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Quercetin	increases expression	1
Silicon Dioxide	decreases expression	1

Clinical trials (associated diseases)

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