RPAP1 (RNA polymerase II associated protein 1) is a 153-kDa scaffolding protein that functions as a critical interface between RNA polymerase II (RNAPII) and regulatory complexes. 1 RPAP1 forms a physical bridge connecting RNAPII to chaperone and assembly factors, facilitating interactions with acetylated histone H3 and enabling proper RNAPII complex assembly. 2 The protein interacts with GPN-loop GTPases and the assembly factor RBA50, coordinating with the Rpb2 subunit during RNAPII biogenesis, with human RPAP1 functioning as the functional analog of yeast Rba50. Genetically, RPAP1 variants associate with lung function variation; exome-wide association studies identified a nonsynonymous variant in RPAP1 predicted to be damaging, significantly associated with forced expiratory volume and vital capacity measures across 111,000+ individuals. 3 Additionally, RPAP1 variants show epistatic interactions with DNA repair pathway genes in breast cancer susceptibility studies. 4 A nonsynonymous RPAP1 mutation was identified as one of six significantly mutated genes in primary gastric linitis plastica. 5 These findings establish RPAP1 as essential for RNAPII assembly and function with broader implications in respiratory and cancer-related phenotypes through both protein-protein interactions and genetic variants.