H4C6 (H4 clustered histone 6) encodes one of fourteen canonical histone H4 genes in humans that produce an invariant histone H4 protein, a core component of nucleosomes essential for chr6 organization and DNA processes including replication, transcription, and repair 1. As part of the histone octamer around which DNA wraps to form nucleosomes, H4C6 plays a fundamental role in chr6 structure and gene regulation 1. De novo missense variants in H4C6 and other H4 genes cause neurodevelopmental disorders characterized by intellectual disability and developmental delays, with variants clustering in regions important for protein-protein interactions with other histone subunits or chaperones 1. Beyond its structural role, H4C6 has emerged as a clinically relevant biomarker through DNA methylation analysis. Hypermethylation of H4C6 serves as a diagnostic biomarker for multiple cancers, including urothelial carcinoma (93% sensitivity when combined with TWIST1) 2, nasopharyngeal carcinoma (86% area under curve, improving to 95% when combined with SEPT9) 3, and lung cancer detection 4. H4C6 protein levels also correlate with bronchopulmonary dysplasia in preterm infants 5. The gene shows involvement in gene-environment interactions affecting brain phenotypes, particularly in response to air pollution exposure 6.