PRKAR1B encodes the regulatory subunit beta (RIβ) of cAMP-dependent protein kinase A (PKA), serving as a critical modulator of cAMP signaling by binding and inhibiting PKA catalytic subunits 1. The protein functions as a homodimer that is protected from aggregation through interaction with catalytic subunits in a dose-dependent manner 2. Mechanistically, PRKAR1B regulates PKA activity through cAMP binding and complex assembly 1. The L50R mutation disrupts RIβ dimerization, causing pathological monomer aggregation that progressively accumulates with age and is accelerated by cAMP signaling, driving age-dependent neurodegeneration 2. Additionally, PRKAR1B generates microprotein-coding isoforms through intronic polyadenylation that are upregulated by genotoxic drugs and promote p53-mediated chemosensitivity 3. Disease associations include Marbach-Schaaf neurodevelopmental syndrome characterized by intellectual disability, autism spectrum disorder, apraxia, and reduced pain sensitivity from de novo missense variants 1. PRKAR1B variants and copy-number gains contribute to adrenocortical disease and Cushing syndrome by decreasing PKA activity 4. The gene also functions as an oncogenic biomarker in head and neck squamous cell carcinoma, with high expression associated with poor prognosis, enhanced tumor proliferation and migration, and potential immunotherapy responsiveness 5. PRKAR1B-AS2 long noncoding RNA promotes ovarian cancer tumorigenesis and chemoresistance via PI3K/AKT/mTOR pathway activation 6.