RHOBTB2 is an atypical Rho-family GTPase that functions as a substrate adapter protein in CUL3-based ubiquitin ligase complexes, regulating protein degradation and cellular processes 1. The protein contains both a GTPase domain and a BTB domain, with distinct functional consequences depending on variant location 2. RHOBTB2 serves as a tumor suppressor in breast cancer, where it inhibits cell migration and invasion through upregulation of BRMS1 and downregulation of ezrin phosphorylation 3. The gene is frequently silenced by promoter hypermethylation in breast cancers, particularly those that are progesterone receptor-negative 4. RHOBTB2 is also a direct target of E2F1 transcription factor and plays roles in cell cycle progression and apoptosis, with expression upregulated during mitosis and drug-induced apoptosis 5. In acute myeloid leukemia, RHOBTB2 promotes cell proliferation by stabilizing KLHL13 protein and modulating Hippo-YAP1 signaling 6. Pathogenic variants cause developmental and epileptic encephalopathy, with missense variants in the BTB domain causing severe early-onset seizures, while GTPase domain variants produce more variable neurodevelopmental phenotypes 2. The epileptic phenotype involves deregulated ion channels and altered neuronal excitability 7.