POLR2C encodes RNA polymerase II subunit C (RPB3), a core component of RNA polymerase II that catalyzes DNA-directed synthesis of mRNA precursors and non-coding RNAs 1. As a structural subunit of the Pol II core complex, POLR2C functions in transcription initiation, elongation, and regulation at Pol II promoters 2. Clinically, POLR2C mutations associate with multiple disease phenotypes. Biallelic variants cause congenital sensorineural hearing loss and male infertility, with a missense mutation (p.Val182Ala) identified in an Iranian family showing prelingual hearing loss and decreased sperm motility 3. Heterozygous nonsense mutations in POLR2C are implicated in primary ovarian insufficiency (POI), with reduced POLR2C expression correlating with impaired cell proliferation 4. Additionally, POLR2C is classified among metabolic function genes associated with nonsyndromic POI 5. Beyond reproductive dysfunction, emerging evidence suggests POLR2C relevance in cancer and neurological disease. POLR2C was identified as a hub gene and prognostic marker in breast cancer, particularly in pyrimidine metabolism pathways, with potential therapeutic targeting combined with immunotherapy 6. In geriatric insomnia, POLR2C emerged as a key molecular signature gene linked to immune processes and nucleocytoplasmic transport 2. Finally, POLR2C-carrying extrachromosomal circular DNA associates with large-artery atherosclerotic stroke risk 7.