ARMC5 is a substrate-recognition component of the BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that functions as a multivalent quality checkpoint in cellular regulation 1. In transcription, the BCR(ARMC5) complex mediates ubiquitination and degradation of RNA Polymerase II phosphorylated at serine-5 of the C-terminal domain, selectively removing defective Pol II complexes at promoter-proximal pause sites 12. This pathway operates in parallel with the Integrator complex to safeguard transcription integrity by preventing incompetent transcripts from entering elongation 2. Beyond transcription, ARMC5 regulates fatty acid metabolism by mediating ubiquitination of SCAP-free SREBF1 and SREBF2, critical transcription factors controlling lipogenic and cholesterol synthesis genes 3. ARMC5 participates in fetal development, T-cell function, and adrenal gland homeostasis 4. Functionally, ARMC5 acts as a tumor suppressor whose loss promotes uncontrolled cell proliferation 4. Clinically, germline inactivating ARMC5 variants account for 20-25% of sporadic primary bilateral macronodular adrenal hyperplasia (PBMAH) cases and up to 80% of familial presentations, causing cortisol excess and Cushing syndrome 56. Comprehensive ARMC5 mutational characterization identifies 146 known germline variants distributed across the coding sequence, providing critical resources for genetic diagnosis and variant interpretation 6.