RNASEH2C encodes the non-catalytic C subunit of the heterotrimeric RNase H2 endonuclease complex, which specifically degrades RNA in RNA:DNA hybrids 1. The protein forms a soluble complex with RNASEH2B that serves as a nucleation site for assembly with the catalytic RNASEH2A subunit to create active RNase H2 enzyme 1. This complex functions processively to hydrolyze various RNA/DNA substrates, likely participating in DNA replication by removing Okazaki fragment RNA primers 1. Mutations in RNASEH2C cause Aicardi-Goutières syndrome type 3 (AGS3), a severe inflammatory encephalopathy characterized by brain calcification, leukoencephalopathy, and elevated type I interferon levels 23. Most AGS-associated RNASEH2C mutations are missense variants, with one founder mutation identified in Pakistani families 3. Interestingly, most AGS-related RNASEH2C mutations retain near-normal enzymatic activity, suggesting the pathogenic mechanism involves functions beyond nuclease activity 1. Recent evidence indicates RNASEH2C may have additional non-enzymatic roles in immune regulation and cancer metastasis, potentially through effects on antigen presentation and adaptive immunity 45. AGS patients consistently show elevated interferon signatures that correlate with disease severity 6.