RHOBTB2

Chr 8AD

Rho related BTB domain containing 2

Also known as: DBC2, DEE64, EIEE64, p83

NCBI Gene: 23221ENSG00000008853UniProt: Q9BYZ6

The protein encoded by this gene is a small Rho GTPase and a candidate tumor suppressor. The encoded protein interacts with the cullin-3 protein, a ubiquitin E3 ligase necessary for mitotic cell division. This protein inhibits the growth and spread of some types of breast cancer. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 64MIM #618004
AD
189
ClinVar variants
8
Pathogenic / LP
0.01
pLI score
0
Active trials
Clinical Summary— RHOBTB2
🧬
Gene-Disease Validity (ClinGen)
complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.29) despite low pLI — interpret in context.
📋
ClinVar Variants
8 Pathogenic / Likely Pathogenic· 104 VUS of 189 total submissions
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esummary.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.50LOEUF
pLI 0.013
Z-score 3.83
OE 0.29 (0.18–0.50)
Moderately constrained

More LoF-intolerant than ~75% 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.
2.66Z-score
OE missense 0.66 (0.60–0.72)
322 obs / 487.2 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.29 (0.18–0.50)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.66 (0.60–0.72)
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.0.97
0≤1.21.6
LoF obs/exp: 10 / 34.1Missense obs/exp: 322 / 487.2Syn Z: 0.38

ClinVar Variant Classifications

189 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7
Likely Pathogenic1
VUS104
Likely Benign71
Benign6
7
Pathogenic
1
Likely Pathogenic
104
VUS
71
Likely Benign
6
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
6
0
7
Likely Pathogenic
0
1
0
0
1
VUS
6
85
13
0
104
Likely Benign
0
7
21
43
71
Benign
0
4
1
1
6
Total7974144189

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

View in ClinVar →

Protein Context — Lollipop Plot

RHOBTB2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

RHOBTB2-related developmental and epileptic encephalopathy

strong
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Developmental and epileptic encephalopathy 64

MIM #618004

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
[Neurodevelopmental impact of a mutation in the RHOBTB2 gene].
Beckers M et al.·Rev Med Liege
2024Review
RHOBTB2 enhances cell proliferation of acute myeloid leukemia by modulating Hippo-YAP1 signaling and dependent of KLHL13.
Liu Y et al.·Sci Rep
2025
Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders.
Langhammer F et al.·Genet Med
2023
Deregulated ion channels contribute to RHOBTB2-associated developmental and epileptic encephalopathy.
Langhammer F et al.·Hum Mol Genet
2025
Characterization of 13 Novel Genetic Variants in Genes Associated with Epilepsy: Implications for Targeted Therapeutic Strategies.
Andjelkovic M et al.·Mol Diagn Ther
2024
Genetic Dystonias: Update on Classification and New Genetic Discoveries.
Keller Sarmiento IJ et al.·Curr Neurol Neurosci Rep
2021Review
Exome sequencing of ATP1A3-negative cases of alternating hemiplegia of childhood reveals SCN2A as a novel causative gene.
Panagiotakaki E et al.·Eur J Hum Genet
2024Cohort
RHOBTB2 Mutations Expand the Phenotypic Spectrum of Alternating Hemiplegia of Childhood.
Zagaglia S et al.·Neurology
2021
Missense Variants in RHOBTB2 Cause a Developmental and Epileptic Encephalopathy in Humans, and Altered Levels Cause Neurological Defects in Drosophila.
Straub J et al.·Am J Hum Genet
2018
A novel tumor suppressor gene RhoBTB2 (DBC2): frequent loss of expression in sporadic breast cancer.
Mao H et al.·Mol Carcinog
2010
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