PHF3 (PHD finger protein 3) is a nuclear transcription regulatory protein that functions as a reader of RNA polymerase II (Pol II) phosphorylation marks. PHF3 contains a SPOC domain that specifically binds phosphorylated serine-2 residues in the Pol II C-terminal domain (CTD), serving as a critical interface between transcription machinery and co-transcriptional regulators 1. Through this interaction, PHF3 drives liquid-liquid phase separation of Pol II, promoting transcription elongation while simultaneously regulating mRNA stability and neuronal gene expression 2. PHF3 knockout cells exhibit increased Pol II stalling and reduced elongation rates, with aberrant derepression of neuronal genes that impairs neural differentiation 2. Clinically, PHF3 shows significant disease relevance across multiple contexts. Expression is frequently reduced or lost in glioblastoma and other astrocytic tumors, correlating with genetic alterations in chromosome 6 3. Notably, glioblastoma patients with anti-PHF3 autoantibodies demonstrate substantially prolonged survival (14.7 months median versus 7.2 months without such antibodies), with PHF3-specific antibody responses detected in >60% of GBM patients 45. Additionally, PHF3-PTP4A1 locus variants show replicable association with alcohol dependence across multiple populations, with SNPs exhibiting cis-acting regulatory effects on PHF3 expression 6. PHF3 mutations have also been identified as immunogenic neoantigens in cancer immunotherapy contexts 7.