GNB1 encodes the β1 subunit of heterotrimeric G proteins, which are essential modulators of transmembrane signaling. The β and γ subunits together are required for GTPase activity, GDP-to-GTP exchange, and G protein–effector interactions across diverse signaling pathways including G protein-coupled receptor signaling and cellular responses to catecholamines and prostaglandins. GNB1 expression is regulated by psychostimulants, reflecting its role in reward circuitry; heritable variation in Gnb1 expression correlates genetically with sensation-seeking behavior and substance use phenotypes in mice 1. In disease contexts, de novo and inherited GNB1 variants cause GNB1 encephalopathy, a rare condition characterized by developmental delay, dystonia, seizures, and nystagmus 2. The leading pathogenic mechanism is neuronal hyperexcitability driven by impaired ion channel regulation; Gβ1γ2 subunits functionally inhibit voltage-gated sodium channels Nav1.1 and Nav1.6 in the brain, and GNB1-E models show reduced GABAergic transmission and decreased sodium current density in parvalbumin-expressing interneurons 3. Additionally, GNB1 truncating and splice variants causing haploinsufficiency are significantly over-represented in syndromic obesity (75% prevalence in this variant class), likely via effects on the hypothalamic leptin-melanocortin pathway 4. Outside neurology, GNB1 overexpression promotes hepatocellular carcinoma progression by activating P38/MAPK signaling via BAG2, and elevated GNB1 expression correlates with poor prognosis in HCC patients 5. Current management of GNB1 encephalopathy relies on deep brain stimulation and intrathecal baclofen pump, pending more definitive targeted therapies.