H4C3 encodes histone H4, a core component of the nucleosome octamer essential for chr6 organization and DNA-dependent processes including replication, transcription, and repair 1. As one of fourteen canonical human H4 genes, H4C3 produces an invariant protein product that interacts with other histone subunits and histone chaperones within the H4 globular domain 1. De novo missense variants in H4C3 and other H4 genes cause a neurodevelopmental syndrome characterized by intellectual disability and motor/developmental delay, with affected amino acids clustering in the H4 core or C-terminal tail 1. Zebrafish studies confirmed pathogenicity, showing abnormal development, defective head organs, and reduced body axis length 1. Beyond neurodevelopment, H4C3 expression alterations associate with multiple pathologies. The protein was upregulated in salivary proteomes of individuals with severe dental fluorosis, correlating with CFTR ion channel dysfunction 2. H4C3 appears in genome-wide analyses of spontaneous abortion, identified as a potential candidate gene for embryonic lethality 3, and ranks among the top 20 differentially expressed genes distinguishing pancreatic cancer from normal tissue 4. Additionally, H4C3 mRNA in blood associates with cognitive decline in Alzheimer's disease patients 5. These findings establish H4C3 variants as pathogenic drivers of neurodevelopmental disease while implicating altered H4C3 expression in cancer, neurodegeneration, and systemic disease.