H3C4 (H3 clustered histone 4) is a histone-encoding gene located on chromosome 6 that plays a role in chr6 structure and gene regulation. H3C4 belongs to the histone H3 family and represents a core component of nucleosomes. The gene has emerged as clinically relevant in two distinct contexts: first, germline variants in H3C4 have been identified in individuals with histonopathies, a rare class of neurodevelopmental disorders caused by mutations in histone-encoding genes 1. Second, H3C4 variants show association with immunotherapy response in non-small cell lung carcinoma, correlating with progression-free survival outcomes in patients treated with immune checkpoint inhibitors 2. Additionally, H3C4 mutations have been detected as enriched variants in clonal hematopoiesis of indeterminate potential (CHIP) within Asian populations, suggesting potential involvement in hematological disease predisposition 3. At the molecular level, H3C4 has been identified as a regulatory target of tRNA-derived small RNAs (tRF-Trp-CCA-014), which bind to the 3'UTR of H3C4 and may modulate its expression in aging processes 4. These findings indicate H3C4 functions in both neurodevelopmental pathways and cancer-related processes, though additional functional studies are needed to fully characterize its mechanisms.