RREB1

Summary

RREB1 (ras responsive element binding protein 1, HGNC:10449) is a protein-coding gene on chromosome 6p24.3, encoding Ras-responsive element-binding protein 1 (Q92766). Transcription factor that binds specifically to the RAS-responsive elements (RRE) of gene promoters.

The protein encoded by this gene is a zinc finger transcription factor that binds to RAS-responsive elements (RREs) of gene promoters. It has been shown that the calcitonin gene promoter contains an RRE and that the encoded protein binds there and increases expression of calcitonin, which may be involved in Ras/Raf-mediated cell differentiation. Multiple transcript variants encoding several different isoforms have been found for this gene.

Source: NCBI Gene 6239 — RefSeq curated summary.

At a glance

• Gene–disease (curated): RASopathy (Moderate, GenCC) — +2 more curated relationships
• GWAS associations: 151
• Clinical variants (ClinVar): 590 total — 2 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 131
• Transcription factor: yes — 11 downstream targets (CollecTRI)
• MANE Select transcript: NM_001003699

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10449
Approved symbol	RREB1
Name	ras responsive element binding protein 1
Location	6p24.3
Locus type	gene with protein product
Status	Approved
Aliases	HNT
Ensembl gene	ENSG00000124782
Ensembl biotype	protein_coding
OMIM	602209
Entrez	6239

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 12 protein_coding, 1 retained_intron

ENST00000334984, ENST00000349384, ENST00000379933, ENST00000379938, ENST00000467782, ENST00000471433, ENST00000475946, ENST00000483150, ENST00000491191, ENST00000852013, ENST00000923507, ENST00000923508, ENST00000923509

RefSeq mRNA: 4 — MANE Select: NM_001003699 NM_001003698, NM_001003699, NM_001003700, NM_001168344

CCDS: CCDS34335, CCDS34336, CCDS54963

Canonical transcript exons

ENST00000379938 — 13 exons

Exon	Start	End
ENSE00001332949	7181124	7181246
ENSE00001332952	7176655	7176773
ENSE00001341554	7248511	7251980
ENSE00001483113	7240438	7240602
ENSE00001529152	7181870	7182082
ENSE00001868424	7107961	7108060
ENSE00003288279	7246424	7247221
ENSE00003395682	7228997	7231907
ENSE00003408308	7211573	7211709
ENSE00003437042	7226467	7226656
ENSE00003522809	7189159	7189322
ENSE00003632853	7210804	7210948
ENSE00003684020	7187434	7187523

Expression profiles

Bgee: expression breadth ubiquitous, 278 present calls, max score 96.92.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.8252 / max 393.9896, expressed in 1814 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
65628	12.1773	1767
65629	5.7802	1589
65633	3.8279	1538
65630	1.7548	924
65635	1.6158	929
65631	0.3658	190
65632	0.2175	86
65634	0.0858	33

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	96.92	gold quality
epithelium of nasopharynx	UBERON:0001951	96.06	gold quality
oral cavity	UBERON:0000167	95.97	gold quality
upper leg skin	UBERON:0004262	95.58	gold quality
sural nerve	UBERON:0015488	95.46	gold quality
pharyngeal mucosa	UBERON:0000355	95.14	gold quality
parotid gland	UBERON:0001831	94.96	gold quality
skin of hip	UBERON:0001554	94.76	gold quality
epithelium of esophagus	UBERON:0001976	94.70	gold quality
esophagus squamous epithelium	UBERON:0006920	94.58	gold quality
mucosa of sigmoid colon	UBERON:0004993	94.38	gold quality
colonic mucosa	UBERON:0000317	94.06	gold quality
mammary duct	UBERON:0001765	93.99	gold quality
trabecular bone tissue	UBERON:0002483	93.90	gold quality
jejunal mucosa	UBERON:0000399	93.78	gold quality
epithelium of mammary gland	UBERON:0003244	93.68	gold quality
oviduct epithelium	UBERON:0004804	93.64	gold quality
colonic epithelium	UBERON:0000397	93.11	gold quality
squamous epithelium	UBERON:0006914	93.09	gold quality
jejunum	UBERON:0002115	93.00	gold quality
body of tongue	UBERON:0011876	92.79	gold quality
penis	UBERON:0000989	92.78	gold quality
nipple	UBERON:0002030	92.74	gold quality
corpus epididymis	UBERON:0004359	92.62	gold quality
lower lobe of lung	UBERON:0008949	92.62	gold quality
gingiva	UBERON:0001828	92.61	gold quality
caput epididymis	UBERON:0004358	92.58	gold quality
bronchial epithelial cell	CL:0002328	92.48	gold quality
mammalian vulva	UBERON:0000997	92.33	gold quality
tongue	UBERON:0001723	92.27	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.41

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

11 targets.

Target	Regulation
CALCA
CCK
CD320	Repression
FSHR	Activation
HBZ	Repression
HLA-G	Unknown
KLK3	Repression
MIR143
SLC39A1	Unknown
SLC39A3	Unknown
TP53	Activation

JASPAR motifs

Motif	Name	Family
MA0073.1	RREB1	Factors with multiple dispersed zinc fingers
MA0073.2	RREB1	Factors with multiple dispersed zinc fingers

JASPAR matrix evidence (PMIDs): PMID:8816445

miRNA regulators (miRDB)

228 targeting RREB1, 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-7110-3P	100.00	73.18	2486
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
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-196A-1-3P	99.99	72.15	2772
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504

Literature-anchored findings (GeneRIF, showing 35)

• The p16 promoter can be downregulated by transfected human RREB, in a Ras- or Mek-dependent manner, and that the BALB/c promoter is more sensitive than DBA/2 to regulation by RREB, a ras-responsive transcriptional element with zinc-finger binding motifs. (PMID:12700664)
• Finb functions as a sequence-specific transcriptional repressor of the hANG gene (PMID:15067362)
• essential to reduce cell-cell adhesion when epithelial cells within an interconnected group undergo dynamic changes in cell shape (PMID:18394891)
• Findings provide evidence that RREB-1 participates in modulating p53 transcription in response to DNA damage. (PMID:19558368)
• Ras pathway and activation of RREB-1 are involved in hZIP1 down-regulation and may play a role in the decrease of the transporter expression in prostate cancer. (PMID:19802870)
• This demonstration is the first of a repressor factor of HLA-G transcriptional activity taking part in HLA-G repression by epigenetic mechanisms. (PMID:19890057)
• KRAS and RREB1 are targets of miR-143/miR-145, revealing a feed-forward mechanism that potentiates Ras signaling (PMID:21159816)
• RREB-1 overexpression results in down-regulation of hZIP1 and contributes to the loss of hZIP1 expression and zinc in prostate cancer. (PMID:21360563)
• Data show that the combination of concurrent zinc, ZIP3, and RREB-1 changes represent early events in the development of adenocarcinoma. (PMID:21613827)
• RREB1 transcription factor splice variants are associated with urologic cancer. (PMID:21703425)
• Data indicate the upregulation of RREB1, PDE6B, and CD209 suggests that these proteins might play important roles in the differentiation of primitive gut tube cells from embryonic stem cells (hESCs) and in primitive gut tube development into pancreas. (PMID:21792086)
• These results support a concept that downregulation of RREB-1 causes downregulation of ZIP3, which results in decreased zinc in pancreatic premalignant and carcinoma cells (PMID:22427155)
• RREB1 is overexpressed in colorectal adenocarcinoma tumors. RREB1 repressed miR-143/145 modulates KRAS signaling. (PMID:22751122)
• Data show the transcriptional activation of the cholecystokinin gene by DJ-1 through interaction of DJ-1 with RREB1 and the effect of DJ-1 on the cholecystokinin level. (PMID:24348900)
• Thus HNT and c are functional homologs at the level of DNA binding, transcriptional regulation and developmental control (PMID:24418439)
• RREB1 is a novel candidate gene for type 2 diabetes associated end-stage kidney disease. (PMID:25027322)
• The pathway of RREB1/ZIP3/Zinc and its downregulation during oncogenesis exist to prevent the accumulation of cytotoxic levels of zinc during the development and progression of the malignant cells in pancreatic adenocarcinoma. (PMID:25050557)
• Histone modifier genes (JMJD1C, RREB1, MINA, KDM7A) alter conotruncal heart phenotypes in 22q11.2 deletion syndrome. (PMID:26608785)
• RREB1 and CCND1 gains are common in nail apparatus melanoma (PMID:27185405)
• RREB1 cooperates with noncoding RNA linc-ADAMTS5 to inhibit ADAMTS5 expression, thereby affecting degeneration of the extracellular matrix (ECM) of the intervertebral disc. (PMID:28341660)
• Of the 465,447 CpG sites analyzed, 12 showed differential methylation (false discovery rate <0.15), including markers within genes associated with monogenic diabetes (HNF4A) or obesity (RREB1). The overall methylation at HNF4A showed inverse correlations with mRNA expression levels, though non significant (PMID:29099273)
• Ectomesenchymal chondromyxoid tumors are characterized by an RREB1-MKL2 fusion gene. (PMID:29912715)
• Functional data indicate that modulating Ras-responsive element-binding protein 1 (RREB1) expression in human DLBCL cell lines in vitro alters KRAS expression, signaling, and proliferation; thus, suggesting that this proto-oncogene is a common mechanism of RAS/MAPK hyperactivation in human DLBCL. (PMID:30355676)
• Data show that RREB1-induced upregulation of AGAP2-AS1 regulates cell proliferation and migration in PC partly through suppressing ANKRD1 and ANGPTL4 by recruiting EZH2. (PMID:30814490)
• Findings demonstrated that RREB1 blocks granulocytic differentiation of myeloid leukemia cells by inhibiting the expression of miR-145 and downstream targets of the RAS signal pathway. (PMID:30982491)
• identification of RAS-responsive element binding protein 1 (RREB1), a RAS transcriptional effector, as a key partner of TGF-beta-activated SMAD transcription factors in epithelial-to-mesenchymal transitions (PMID:31915377)
• Transcription Factor RREB1: from Target Genes towards Biological Functions. (PMID:32210733)
• Haploinsufficiency of RREB1 causes a Noonan-like RASopathy via epigenetic reprogramming of RAS-MAPK pathway genes. (PMID:32938917)
• Knockdown of RREB1 inhibits cell proliferation via enhanced p16 expression in gastric cancer. (PMID:34666611)
• RREB1 promotes the development of parafollicular carcinogenesis through the Ras-Raf-1-ELK3 signaling pathway. (PMID:35737446)
• Loss of RREB1 in pancreatic beta cells reduces cellular insulin content and affects endocrine cell gene expression. (PMID:36633628)
• The U2AF65/circNCAPG/RREB1 feedback loop promotes malignant phenotypes of glioma stem cells through activating the TGF-beta pathway. (PMID:36635261)
• LncRNA SNHG4 promotes prostate cancer cell survival and resistance to enzalutamide through a let-7a/RREB1 positive feedback loop and a ceRNA network. (PMID:37596700)
• A novel interaction between RNA m[6]A methyltransferase METTL3 and RREB1. (PMID:39278095)
• RREB1 could act as an immunological and prognostic biomarker: From comprehensive analysis to osteosarcoma validation. (PMID:39405927)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rreb1b	ENSDARG00000042652
danio_rerio	rreb1a	ENSDARG00000063701
mus_musculus	Rreb1	ENSMUSG00000039087
rattus_norvegicus	Rreb1	ENSRNOG00000015701
drosophila_melanogaster	peb	FBGN0003053

Paralogs (14): HIVEP2 (ENSG00000010818), HIVEP1 (ENSG00000095951), SALL4 (ENSG00000101115), ZNF516 (ENSG00000101493), SALL1 (ENSG00000103449), BCL11A (ENSG00000119866), ZNF831 (ENSG00000124203), HIVEP3 (ENSG00000127124), BCL11B (ENSG00000127152), ZNF219 (ENSG00000165804), SALL2 (ENSG00000165821), ZNF217 (ENSG00000171940), ZNF536 (ENSG00000198597), SALL3 (ENSG00000256463)

Protein

Protein identifiers

Ras-responsive element-binding protein 1 — Q92766 (reviewed: Q92766)

Alternative names: Finger protein in nuclear bodies, Raf-responsive zinc finger protein LZ321, Zinc finger motif enhancer-binding protein 1

All UniProt accessions (4): C9JE09, C9JPJ6, C9JU34, Q92766

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that binds specifically to the RAS-responsive elements (RRE) of gene promoters. Represses the angiotensinogen gene. Negatively regulates the transcriptional activity of AR. Potentiates the transcriptional activity of NEUROD1. Promotes brown adipocyte differentiation. May be involved in Ras/Raf-mediated cell differentiation by enhancing calcitonin expression.

Subunit / interactions. Interacts with NEUROD1. Interacts with AR.

Subcellular location. Nucleus speckle.

Tissue specificity. Expressed in heart, placenta, lung, liver, skeletal muscle, kidney and pancreas. Not found in the brain.

Similarity. Belongs to the krueppel C2H2-type zinc-finger protein family.

Isoforms (6)

UniProt ID	Names	Canonical?
Q92766-1	1, beta	yes
Q92766-2	2, alpha
Q92766-3	3, gamma
Q92766-4	4
Q92766-5	5, delta
Q92766-6	6, epsilon

RefSeq proteins (4): NP_001003698, NP_001003699, NP_001003700, NP_001161816 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013087	Znf_C2H2_type	Domain
IPR036236	Znf_C2H2_sf	Homologous_superfamily
IPR052795	RREB1	Family

Pfam: PF00096, PF13912

UniProt features (97 total): modified residue 22, zinc finger region 15, compositionally biased region 15, cross-link 13, region of interest 9, sequence conflict 9, splice variant 7, sequence variant 6, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92766-F1	48.28	0.00

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (35): 36, 42, 161, 175, 180, 231, 970, 1122, 1134, 1135, 1140, 1167, 1174, 1175, 1219, 1225, 1315, 1320, 1475, 1585 …

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 736 (showing top): MORF_ITGA2, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, CAR_TNFRSF25, HNF3ALPHA_Q6, GOBP_REGULATION_OF_MAMMARY_GLAND_EPITHELIAL_CELL_PROLIFERATION, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_REGULATION_OF_WOUND_HEALING, MORF_MSH3, MIDORIKAWA_AMPLIFIED_IN_LIVER_CANCER, chr6p24, GOBP_POSITIVE_REGULATION_OF_FAT_CELL_DIFFERENTIATION, MORF_BRCA1, GOBP_MAMMARY_GLAND_EPITHELIUM_DEVELOPMENT

GO Biological Process (14): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), positive regulation of epithelial cell migration (GO:0010634), positive regulation of mammary gland epithelial cell proliferation (GO:0033601), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of brown fat cell differentiation (GO:0090336), positive regulation of substrate adhesion-dependent cell spreading (GO:1900026), positive regulation of wound healing, spreading of epidermal cells (GO:1903691), positive regulation of lamellipodium morphogenesis (GO:2000394), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of developmental process (GO:0051094)

GO Molecular Function (7): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), zinc ion binding (GO:0008270), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), metal ion binding (GO:0046872)

GO Cellular Component (6): fibrillar center (GO:0001650), nucleus (GO:0005634), cytoplasm (GO:0005737), nuclear body (GO:0016604), nuclear speck (GO:0016607), extracellular exosome (GO:0070062)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA-templated transcription	4
regulation of DNA-templated transcription	4
transcription by RNA polymerase II	3
regulation of transcription by RNA polymerase II	2
positive regulation of cell migration	2
positive regulation of developmental process	2
transcription cis-regulatory region binding	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
cellular anatomical structure	2
negative regulation of DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
epithelial cell migration	1
regulation of epithelial cell migration	1
mammary gland epithelial cell proliferation	1
regulation of mammary gland epithelial cell proliferation	1
positive regulation of epithelial cell proliferation	1
positive regulation of multicellular organismal process	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
positive regulation of fat cell differentiation	1
brown fat cell differentiation	1
regulation of brown fat cell differentiation	1
positive regulation of cell-substrate adhesion	1
substrate adhesion-dependent cell spreading	1
regulation of substrate adhesion-dependent cell spreading	1
wound healing, spreading of epidermal cells	1
positive regulation of wound healing	1
regulation of wound healing, spreading of epidermal cells	1
lamellipodium morphogenesis	1
positive regulation of lamellipodium organization	1
regulation of lamellipodium morphogenesis	1
negative regulation of RNA biosynthetic process	1
developmental process	1
positive regulation of biological process	1
regulation of developmental process	1
cis-regulatory region sequence-specific DNA binding	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1

Protein interactions and networks

STRING

1361 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RREB1	KDM1A	O60341	715
RREB1	KAT2B	Q92831	666
RREB1	CTBP1	Q13363	609
RREB1	HRAS	P01112	577
RREB1	MYC	P01106	568
RREB1	RCOR1	Q9UKL0	533
RREB1	HMG20A	Q9NP66	503
RREB1	INHBC	P55103	494
RREB1	CREB1	P16220	482
RREB1	PHF21B	Q96EK2	479
RREB1	GTF2I	P78347	476
RREB1	HDAC1	Q13547	475
RREB1	ZMYM3	Q14202	467
RREB1	HMG20B	Q9P0W2	459
RREB1	USF1	P22415	457

IntAct

95 interactions, top by confidence:

A	B	Type	Score
HDAC2	KDM1A	psi-mi:“MI:0914”(association)	0.890
HDAC1	CDK2AP1	psi-mi:“MI:0914”(association)	0.840
HDAC1	TNRC18	psi-mi:“MI:0914”(association)	0.790
NAPA	SNAP23	psi-mi:“MI:0914”(association)	0.780
HDAC1	ZNF609	psi-mi:“MI:0914”(association)	0.730
CTBP1	CBX4	psi-mi:“MI:0914”(association)	0.700
NFIC	NFIB	psi-mi:“MI:2364”(proximity)	0.690
HDAC3	KDM1A	psi-mi:“MI:0914”(association)	0.650
BAG2	HGS	psi-mi:“MI:0914”(association)	0.530
SFMBT1	KDM1A	psi-mi:“MI:0914”(association)	0.530
ARL6	SART1	psi-mi:“MI:0914”(association)	0.510
NEK7	P4HA2	psi-mi:“MI:0914”(association)	0.510
RREB1	HDAC3	psi-mi:“MI:0403”(colocalization)	0.510
RREB1	HDAC3	psi-mi:“MI:0914”(association)	0.510
RREB1	PRPF8	psi-mi:“MI:0915”(physical association)	0.400
Snw1	AKR7A2	psi-mi:“MI:0914”(association)	0.350
Cdc23	ANAPC15	psi-mi:“MI:0914”(association)	0.350
Ppp4c	NAP1L1	psi-mi:“MI:0914”(association)	0.350
SNCA	SRRM1	psi-mi:“MI:0914”(association)	0.350
HDAC1	TRAK1	psi-mi:“MI:0914”(association)	0.350
GRHL1	POLRMT	psi-mi:“MI:0914”(association)	0.350
HDAC1		psi-mi:“MI:0914”(association)	0.350
HDAC2		psi-mi:“MI:0914”(association)	0.350
H2BC21	SMCHD1	psi-mi:“MI:0914”(association)	0.350
TEX19	ZNF316	psi-mi:“MI:0914”(association)	0.350
RCOR1	ZBTB5	psi-mi:“MI:0914”(association)	0.350
PIAS4	TRIM24	psi-mi:“MI:0914”(association)	0.350
SPATA20	HDAC4	psi-mi:“MI:0914”(association)	0.350

BioGRID (130): RREB1 (Affinity Capture-MS), RREB1 (Synthetic Growth Defect), RREB1 (Affinity Capture-MS), RREB1 (Affinity Capture-MS), RREB1 (Affinity Capture-MS), RREB1 (Affinity Capture-MS), RREB1 (Affinity Capture-MS), RREB1 (Affinity Capture-MS), RREB1 (Affinity Capture-MS), RREB1 (Affinity Capture-MS), ARL6 (Affinity Capture-MS), NEK7 (Affinity Capture-MS), TOR1AIP2 (Affinity Capture-MS), RREB1 (Affinity Capture-RNA), RREB1 (Affinity Capture-MS)

ESM2 similar proteins: A0JPB4, A0PJY2, B0K011, O08876, O15090, O57415, O62651, O70237, O75626, O95863, P19544, P22561, P41183, P49952, P55878, P86413, Q02085, Q08DS3, Q0IHB8, Q0P4W9, Q0VDQ9, Q25C93, Q28G88, Q2TAR3, Q2VWH6, Q32NK7, Q3MHQ4, Q3T135, Q3UH06, Q567J8, Q5T0B9, Q5VTD9, Q5XJQ7, Q60636, Q62255, Q66JF8, Q6AY34, Q6DBW0, Q6NRM0, Q804Q5

Diamond homologs: A0JC51, A2ANX9, O15391, O57311, O57415, O60481, O62836, O73689, O95409, P08048, P0C6P6, P10925, P17010, P17012, P18747, P20662, P22227, P25490, P34694, P46684, P80944, Q00899, Q10RP4, Q12145, Q15915, Q29419, Q2FAY8, Q3TTC2, Q3UH06, Q3US17, Q3Y4E1, Q52V16, Q5NVT2, Q5R782, Q5RJ54, Q61467, Q61624, Q62520, Q62521, Q62806

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
RREB1	“down-regulates quantity by repression”	KLK3	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 120 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
SUMOylation of transcription cofactors	5	15.2×	1e-03
Regulation of PTEN gene transcription	6	13.4×	5e-04
mRNA 3’-end processing	5	12.3×	2e-03
Negative Regulation of CDH1 Gene Transcription	7	10.5×	5e-04
SUMOylation of chromatin organization proteins	5	9.9×	4e-03
mRNA Splicing	7	9.6×	5e-04
Transport of Mature mRNA derived from an Intron-Containing Transcript	5	9.5×	5e-03
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	5	9.2×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein sumoylation	5	14.7×	2e-03
mRNA splicing, via spliceosome	10	8.3×	7e-05
RNA splicing	8	6.4×	3e-03
transcription by RNA polymerase II	9	5.8×	2e-03
mRNA processing	8	5.7×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	374
Likely benign	138
Benign	29

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
2578519	NM_001003699.4(RREB1):c.2677del (p.Ala893fs)	Pathogenic
3693509	NM_001003699.4(RREB1):c.777_780del (p.Lys259fs)	Pathogenic
4822029	NM_001003700.2(RREB1):c.3974-2087_3974-2084del	Likely pathogenic

SpliceAI

3204 predictions. Top by Δscore:

Variant	Effect	Δscore
6:7181210:A:T	donor_gain	1.0000
6:7187430:TTAG:T	acceptor_loss	1.0000
6:7187431:TAG:T	acceptor_loss	1.0000
6:7187432:A:AG	acceptor_gain	1.0000
6:7187432:AG:A	acceptor_gain	1.0000
6:7187432:AGGA:A	acceptor_loss	1.0000
6:7187433:G:A	acceptor_loss	1.0000
6:7187433:G:GA	acceptor_gain	1.0000
6:7187433:GG:G	acceptor_gain	1.0000
6:7187433:GGA:G	acceptor_gain	1.0000
6:7187433:GGAA:G	acceptor_gain	1.0000
6:7187520:CCAGG:C	donor_loss	1.0000
6:7187522:AGG:A	donor_loss	1.0000
6:7187525:T:G	donor_loss	1.0000
6:7189154:TGCA:T	acceptor_loss	1.0000
6:7189156:CA:C	acceptor_loss	1.0000
6:7189157:A:AG	acceptor_gain	1.0000
6:7189157:A:G	acceptor_loss	1.0000
6:7189158:G:A	acceptor_loss	1.0000
6:7189158:G:GA	acceptor_gain	1.0000
6:7189158:GC:G	acceptor_gain	1.0000
6:7189158:GCAC:G	acceptor_gain	1.0000
6:7189158:GCACA:G	acceptor_gain	1.0000
6:7210894:GAAAC:G	donor_gain	1.0000
6:7210941:C:G	donor_gain	1.0000
6:7211568:CTCA:C	acceptor_loss	1.0000
6:7211569:TCA:T	acceptor_loss	1.0000
6:7211571:AGAT:A	acceptor_gain	1.0000
6:7211572:G:GC	acceptor_loss	1.0000
6:7211572:GATG:G	acceptor_gain	1.0000

AlphaMissense

11434 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:7187464:T:C	C68R	1.000
6:7187504:T:C	L81P	1.000
6:7189192:T:C	C99R	1.000
6:7189194:C:G	C99W	1.000
6:7189201:T:C	C102R	1.000
6:7189202:G:A	C102Y	1.000
6:7189203:C:G	C102W	1.000
6:7189225:A:C	S110R	1.000
6:7189227:C:A	S110R	1.000
6:7189227:C:G	S110R	1.000
6:7189232:T:C	L112P	1.000
6:7189237:C:A	R114S	1.000
6:7189238:G:C	R114P	1.000
6:7189240:C:A	H115N	1.000
6:7189240:C:G	H115D	1.000
6:7189242:C:A	H115Q	1.000
6:7189242:C:G	H115Q	1.000
6:7189247:T:C	L117P	1.000
6:7189276:T:C	C127R	1.000
6:7189285:T:C	C130R	1.000
6:7189297:T:A	F134I	1.000
6:7189297:T:C	F134L	1.000
6:7189298:T:C	F134S	1.000
6:7189298:T:G	F134C	1.000
6:7189299:T:A	F134L	1.000
6:7189299:T:G	F134L	1.000
6:7189304:C:T	T136I	1.000
6:7189309:G:A	G138R	1.000
6:7189309:G:C	G138R	1.000
6:7189309:G:T	G138W	1.000

dbSNP variants (sampled 300 via entrez): RS1000003073 (6:7213120 A>T), RS1000016500 (6:7199249 G>T), RS1000036234 (6:7121754 T>C), RS1000038055 (6:7159190 A>C), RS1000040590 (6:7107514 T>C,G), RS1000116092 (6:7203729 C>T), RS1000116669 (6:7204902 A>G), RS1000139656 (6:7136738 A>C), RS1000167143 (6:7203968 T>A,C), RS1000167710 (6:7175112 CTTTT>C,CTTT,CTTTTT), RS1000176596 (6:7140905 T>A), RS1000197276 (6:7242281 C>A,G,T), RS1000211504 (6:7247322 C>A,T), RS1000213005 (6:7181678 C>G,T), RS1000219313 (6:7121623 G>C,T)

Disease associations

OMIM: gene MIM:602209 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
RASopathy	Moderate	Autosomal dominant
22q11.2 deletion syndrome	Supportive	Autosomal dominant
complex neurodevelopmental disorder	Limited	Autosomal dominant

Mondo (4): microcephaly (MONDO:0001149), complex neurodevelopmental disorder (MONDO:0100038), 22q11.2 deletion syndrome (MONDO:0018923), RASopathy (MONDO:0021060)

Orphanet (0):

HPO phenotypes

131 total (30 of 131 shown, HPO-id order):

HPO	Term
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000076	Vesicoureteral reflux
HP:0000089	Renal hypoplasia
HP:0000113	Polycystic kidney dysplasia
HP:0000130	Abnormality of the uterus
HP:0000160	Narrow mouth
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000262	Turricephaly
HP:0000272	Malar flattening
HP:0000276	Long face
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000385	Small earlobe
HP:0000389	Chronic otitis media
HP:0000396	Overfolded helix
HP:0000405	Conductive hearing impairment
HP:0000414	Bulbous nose
HP:0000426	Prominent nasal bridge
HP:0000431	Wide nasal bridge
HP:0000453	Choanal atresia

GWAS associations

151 associations (top):

Study	Trait	p-value
GCST000653_3	Age-related macular degeneration	1.000000e-06
GCST000818_1	Urate levels	1.000000e-09
GCST001198_75	Multiple sclerosis	3.000000e-06
GCST001523_20	Visceral adipose tissue adjusted for BMI	4.000000e-06
GCST001523_22	Visceral adipose tissue adjusted for BMI	4.000000e-06
GCST001527_11	Fasting blood glucose (BMI interaction)	3.000000e-07
GCST001776_11	Cardiac Troponin-T levels	1.000000e-06
GCST001791_34	Urate levels	1.000000e-23
GCST002138_1	Waist-hip ratio	3.000000e-08
GCST002352_15	Type 2 diabetes	1.000000e-09
GCST003784_8	Multiple system atrophy	3.000000e-06
GCST003967_1	Visceral adipose tissue adjusted for BMI	1.000000e-08
GCST003967_2	Visceral adipose tissue adjusted for BMI	6.000000e-09
GCST003973_1	Visceral adipose tissue/subcutaneous adipose tissue ratio adjusted for BMI	9.000000e-06
GCST004075_1	Vertical cup-disc ratio	2.000000e-08
GCST004075_2	Vertical cup-disc ratio	2.000000e-10
GCST004601_68	Red blood cell count	6.000000e-12
GCST004604_102	Hematocrit	6.000000e-14
GCST004610_7	White blood cell count	2.000000e-12
GCST004611_85	High light scatter reticulocyte count	5.000000e-09
GCST004615_27	Hemoglobin concentration	2.000000e-11
GCST004619_71	Reticulocyte fraction of red cells	7.000000e-11
GCST004620_58	Sum basophil neutrophil counts	4.000000e-09
GCST004622_185	Reticulocyte count	4.000000e-11
GCST004625_20	Monocyte count	5.000000e-12
GCST004625_21	Monocyte count	3.000000e-09
GCST004626_87	Myeloid white cell count	4.000000e-09
GCST004627_69	Lymphocyte count	3.000000e-10
GCST004629_74	Neutrophil count	3.000000e-09
GCST005186_13	Fasting blood glucose	1.000000e-06

EFO canonical traits (36, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement
EFO:0004340	body mass index
EFO:0005043	cardiac troponin T measurement
EFO:0004343	waist-hip ratio
EFO:0004767	visceral:subcutaneous adipose tissue ratio
EFO:0006939	cup-to-disc ratio measurement
EFO:0004305	erythrocyte count
EFO:0004348	hematocrit
EFO:0007986	reticulocyte count
EFO:0004509	hemoglobin measurement
EFO:0004833	neutrophil count
EFO:0005090	basophil count
EFO:0005091	monocyte count
EFO:0004587	lymphocyte count
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0009270	heel bone mineral density
EFO:0005763	pulse pressure measurement
EFO:0004761	uric acid measurement
EFO:0009104	hyperuricemia
EFO:0009924	Drugs used in diabetes use measurement
EFO:0004344	birth weight
EFO:0005939	parental genotype effect measurement
EFO:0010459	aminoadipic acid measurement
EFO:0010421	triacylglycerol 54:3 measurement
EFO:0010358	lysophosphatidylcholine 16:1 measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004530	triglyceride measurement
EFO:0004468	glucose measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, affects cotreatment, increases expression	7
trichostatin A	affects cotreatment, increases expression, affects expression	3
Arsenic	affects cotreatment, increases abundance, increases expression, decreases expression, affects methylation	3
bisphenol A	affects cotreatment, increases methylation, decreases methylation, increases expression	2
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	affects methylation, increases mutagenesis	2
Cisplatin	decreases expression	2
Estradiol	increases expression	2
GSK-J4	increases expression	1
TAK-243	decreases sumoylation	1
dicrotophos	increases expression	1
potassium perchlorate	decreases expression	1
titanium dioxide	decreases methylation	1
arsenite	affects binding, decreases reaction	1
mono-(2-ethylhexyl)phthalate	decreases methylation, increases abundance	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
benzo(e)pyrene	increases methylation	1
coumarin	decreases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
corosolic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Vorinostat	affects cotreatment, increases expression	1
Leflunomide	increases expression	1
Acetaminophen	decreases expression	1
Vehicle Emissions	decreases expression, increases abundance	1
Cadmium	increases expression	1

Cellosaurus cell lines

4 cell lines: 3 embryonic stem cell, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A5X6	SEES3-1V human RREB1, clone1	Embryonic stem cell	Male
CVCL_A5X7	SEES3-1V human RREB1, clone2	Embryonic stem cell	Male
CVCL_A5X8	SEES3-1V human RREB1, clone3	Embryonic stem cell	Male
CVCL_XV78	HEK293 eGFP-RREB1	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00395538	PHASE3	TERMINATED	Effects of PTH Replacement on Bone in Hypoparathyroidism
NCT00576407	PHASE2	COMPLETED	Thymus Transplantation in DiGeorge Syndrome #668
NCT00576836	PHASE2	COMPLETED	Thymus Transplantation Dose in DiGeorge #932
NCT01821781	PHASE2	ACTIVE_NOT_RECRUITING	Immune Disorder HSCT Protocol
NCT05149898	PHASE2	COMPLETED	Open-Label Study of ZYN002 Administered as a Transdermal Gel to Children and Adolescents With 22q11.2 Deletion Syndrome (INSPIRE)
NCT07284641	PHASE2	RECRUITING	Hematopoietic Stem Cell Transplantation (HSCT) for Common Variable Immunodeficiency (CVID) and Other Autoimmune Manifestations of Primary Immune Regulatory Disorders (PIRD)
NCT00566488	PHASE1	COMPLETED	Parathyroid and Thymus Transplantation in DiGeorge #931
NCT00579709	PHASE1	COMPLETED	Thymus Transplantation With Immunosuppression
NCT02895906	PHASE1	COMPLETED	Safety and Efficacy Study of NFC-1 in Subjects Aged 12-17 Years With 22q11.2DS & Associated Neuropsychiatric Conditions
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
NCT00004351	Not specified	COMPLETED	Study of Phenotype and Genotype Correlations in Patients With Contiguous Gene Deletion Syndromes
NCT00005102	Not specified	UNKNOWN	Immunologic Evaluation in Patients With DiGeorge Syndrome or Velocardiofacial Syndrome
NCT00105274	Not specified	COMPLETED	Velocardiofacial (VCFS; 22q11.2; DiGeorge) Syndrome Study
NCT00161109	Not specified	UNKNOWN	Genetics and Psychopathology in the 22q11 Deletion Syndrome
NCT00278005	Not specified	TERMINATED	Infection in DiGeorge Following CHD Surgery
NCT00556530	Not specified	RECRUITING	Examining Genetic Factors That Affect the Severity of 22q11.2 Deletion Syndrome
NCT00916955	Not specified	COMPLETED	Genetic Modifiers for 22q11.2 Syndrome
NCT01220531	Not specified	COMPLETED	Thymus Transplantation Safety-Efficacy
NCT01781923	Not specified	COMPLETED	Cognitive Remediation in 22q11DS
NCT02381457	Not specified	COMPLETED	SNP-based Microdeletion and Aneuploidy RegisTry (SMART)
NCT02430584	Not specified	UNKNOWN	Whole Blood Specimen Collection From Pregnant Subjects
NCT02460328	Not specified	COMPLETED	Resolution of Primary Immune Defect in 22q11.2 Deletion Syndrome
NCT02787486	Not specified	COMPLETED	Expanded Noninvasive Genomic Medical Assessment: The Enigma Study
NCT03284060	Not specified	TERMINATED	Social Cognition Training and Cognitive Remediation
NCT03836300	Not specified	ENROLLING_BY_INVITATION	Parent and Infant Inter(X)Action Intervention (PIXI)
NCT04373226	Not specified	TERMINATED	Arithmetic Abilities in Children With 22q11.2DS
NCT04639388	Not specified	RECRUITING	Understanding of Psychotic Disorders in Children With 22q11.2DS
NCT04639960	Not specified	TERMINATED	Neuroprotective Effects of Risperdal on Brain and Cognition in 22q11 Deletion Syndrome
NCT04647500	Not specified	COMPLETED	Effects of Methylphenidate on Brain and Cognition in 22q11 Deletion Syndrome
NCT05924347	Not specified	RECRUITING	Early Scoliotic Changes in Children at Increased Risk for Scoliosis Development
NCT07493096	Not specified	RECRUITING	Intensive Multimodal Neurorehabilitation Targeting Neuroplasticity in Pediatric Neurodevelopmental and Chromosomal Disorders
NCT04888936	Not specified	RECRUITING	Clinical, Genetic, and Epidemiologic Study of Children and Adults With RASopathies
NCT05761314	Not specified	RECRUITING	Solid Tumors in RASopathies
NCT06331117	Not specified	UNKNOWN	Effect of RAS/MAPK Pathway Hyperactivation on Growth’ and Bone’ Profile of the RASopathies
NCT06355622	Not specified	UNKNOWN	Prevalence and Characterization of Pain in RASopathies
NCT06489067	Not specified	RECRUITING	Study of the Thyroid Function and Echostructural Morphology in Patients Affected With Rasopathies (ECORAS2023)
NCT06776380	Not specified	RECRUITING	Pubertal Development in Patients with RASopathies
NCT07005297	Not specified	NOT_YET_RECRUITING	Clinical Genetics Branch Eligibility Screening Survey
NCT07344480	Not specified	RECRUITING	Retrospective Natural History Study of RASopathy-associated Cardiomyopathy (RAS-CM)