RNASEH2B encodes a non-catalytic subunit of ribonuclease H2, an endonuclease complex that degrades RNA in RNA:DNA hybrids and removes ribonucleotides from genomic DNA 1. The protein functions in DNA replication by facilitating removal of Okazaki fragment RNA primers and participates in ribonucleotide excision repair 1. Loss of RNASEH2B function leads to accumulation of genomic ribonucleotides, which become substrates for topoisomerase 1 cleavage, resulting in PARP-trapping DNA lesions that impede replication 1. Mutations in RNASEH2B cause Aicardi-Goutières syndrome type 2 (AGS2), a severe inflammatory encephalopathy characterized by interferon overproduction due to cytosolic nucleic acid accumulation 23. Patients with RNASEH2B mutations typically present with later disease onset and better neurological preservation compared to other AGS subtypes, with lower mortality rates (8.0% vs 34.3%) 4. The protein loss creates therapeutic vulnerabilities, as RNASEH2B-deficient cells show hypersensitivity to PARP inhibitors, potentially exploitable in cancers with RNASEH2B deletions 15. Clinical diagnosis can be supported by elevated interferon-stimulated gene expression, though patients with RNASEH2B mutations may show negative interferon signatures in some cases 6.