RREB1

Chr 6

ras responsive element binding protein 1

NCBI Gene: 6239ENSG00000124782UniProt: Q92766

Transcription factor that binds specifically to the RAS-responsive elements (RRE) of gene promoters (PubMed:10390538, PubMed:15067362, PubMed:17550981, PubMed:8816445, PubMed:9305772). Represses the angiotensinogen gene (PubMed:15067362). Negatively regulates the transcriptional activity of AR (PubMed:17550981). Potentiates the transcriptional activity of NEUROD1 (PubMed:12482979). Promotes brown adipocyte differentiation (By similarity). May be involved in Ras/Raf-mediated cell differentiation by enhancing calcitonin expression (PubMed:8816445)

574
ClinVar variants
13
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— RREB1
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
13 Pathogenic / Likely Pathogenic· 380 VUS of 574 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.16LOEUF
pLI 1.000
Z-score 6.13
OE 0.06 (0.03–0.16)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

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.
-0.43Z-score
OE missense 1.04 (0.99–1.09)
1135 obs / 1095.3 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.0.06 (0.03–0.16)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.04 (0.99–1.09)
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.1.33
0≤1.21.6
LoF obs/exp: 3 / 49.6Missense obs/exp: 1135 / 1095.3Syn Z: -5.74

ClinVar Variant Classifications

574 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12
Likely Pathogenic1
VUS380
Likely Benign144
Benign30
Conflicting7
12
Pathogenic
1
Likely Pathogenic
380
VUS
144
Likely Benign
30
Benign
7
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
0
10
0
12
Likely Pathogenic
0
0
1
0
1
VUS
5
352
23
0
380
Likely Benign
0
38
5
101
144
Benign
0
11
1
18
30
Conflicting
—7
Total740140119574

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

View in ClinVar →

Protein Context — Lollipop Plot

RREB1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

RREB1-related RASopathy syndrome with congenital heart disease, genitourinary malformations, and developmental delay

limited
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗
frameshift variant

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
LncRNA SNHG4 promotes prostate cancer cell survival and resistance to enzalutamide through a let-7a/RREB1 positive feedback loop and a ceRNA network.
Dong Q et al.·J Exp Clin Cancer Res
2023
Selective translation of nuclear mitochondrial respiratory proteins reprograms succinate metabolism in AML development and chemoresistance.
Han G et al.·Cell Stem Cell
2024
Transcription Factor RREB1: from Target Genes towards Biological Functions.
Deng YN et al.·Int J Biol Sci
2020Review
RREB1 could act as an immunological and prognostic biomarker: From comprehensive analysis to osteosarcoma validation.
Zhang Z et al.·Int Immunopharmacol
2024
The first case of a point pathogenic variant in the RREB1 gene in Noonan-like Rasopathy.
Shatokhina O et al.·Clin Genet
2024Case report
First Report of a Novel Pathogenic Variant in the RREB1 Gene Associated With Obesity and Metabolic Syndrome.
Mammadova N et al.·Clin Genet
2026Case report
Clinical, Morphologic, and Genomic Findings in Spitz Tumors With RET Fusion: A Series of 31 Cases.
Donati M et al.·Mod Pathol
2025Cohort
Somatic Genomic Profiling of Pancreatic Ductal Adenocarcinomas From a Diverse Cohort of Patients.
Riner AN et al.·Pancreas
2025Cohort
Haploinsufficiency of RREB1 causes a Noonan-like RASopathy via epigenetic reprogramming of RAS-MAPK pathway genes.
Kent OA et al.·Nat Commun
2020
RREB1::MRTFB fusion-positive extra-glossal mesenchymal neoplasms: A series of five cases expanding their anatomic distribution and highlighting significant morphological and phenotypic diversity.
Agaimy A et al.·Genes Chromosomes Cancer
2023Cohort
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.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools