RNASEH2A encodes the catalytic subunit of RNase H2, an endonuclease that removes RNA from RNA:DNA hybrids and excises single ribonucleotides from DNA 1. The enzyme plays critical roles in DNA replication through removal of lagging-strand Okazaki fragment RNA primers and participates in DNA damage repair processes 1. RNASEH2A is primarily associated with Aicardi-Goutières syndrome (AGS), a rare monogenic type I interferonopathy caused by biallelic RNASEH2A mutations that lead to self-nucleic acid accumulation and aberrant cytoplasmic nucleic acid sensing 2. Patients with RNASEH2A mutations present with encephalopathy, basal ganglia calcification, and elevated interferon-α levels, with mutations accounting for approximately 2-5% of AGS cases and showing higher mortality (34.3%) compared to other AGS genes 34. Beyond AGS, RNASEH2A downregulation during cellular senescence promotes inflammatory gene expression through genomic DNA fragmentation and nucleotide ligand accumulation, contributing to age-related pathologies and cancer progression 5. Additionally, RNASEH2A expression correlates with proliferation and apoptosis pathways in glioblastoma and renal cell carcinoma, making it a potential prognostic biomarker for cancer outcomes 67.