POLR2F (RNA polymerase II, I and III subunit F) is a shared catalytic subunit of RNA polymerases I, II, and III, enabling transcription of ribosomal RNA precursors, mRNA, and functional non-coding RNAs [UniProt/GO]. Structurally, POLR2F comprises part of the clamp element in Pol II, forming a binding pocket with POLR2A and POLR2B for the POLR2D-POLR2G subcomplex [UniProt]. Beyond its core transcriptional role, POLR2F has emerged as a multi-disease biomarker. Genetically predicted elevated POLR2F levels associate with increased risk of psoriatic arthritis 1 and are positively associated with chr22 kidney disease, heart failure, coronary heart disease, and stroke, with Mendelian randomization supporting causal association with coronary heart disease 2. In colorectal cancer, POLR2F upregulation correlates with improved 3-year survival 3, though it was identified as a potential drug repurposing target 4. In glioblastoma, reduced POLR2F expression correlates with shorter overall survival 5. POLR2F was identified as a novel candidate gene for periventricular white matter hyperintensities 6 and serves as a stable housekeeping gene in Parkinson's disease research 7. These findings suggest POLR2F has disease-specific roles beyond transcription, warranting further investigation as a biomarker and potential therapeutic target.