H4C5 encodes histone H4, a core component of nucleosomes that organizes DNA and supports essential cellular processes including DNA replication, transcription, and repair 1. As one of fourteen canonical H4 genes in humans, H4C5 produces an invariant histone protein despite nucleotide-level variation across family members 1. De novo missense variants in H4C5 cause a neurodevelopmental syndrome characterized by intellectual disability and developmental delay, with variable features including microcephaly, short stature, and facial dysmorphisms 21. These pathogenic variants cluster in the H4 core globular domain and C-terminal tail where protein-protein interactions occur with other histones and histone chaperones 1. At least seven disease-causing H4C5 missense variants have been identified 2. Functional studies in zebrafish embryos demonstrated that H4 variants cause abnormal development, defective head organs, and reduced body axis length, confirming causality 1. Recent research identified H4C5 as a component of a urine biomarker panel for prostate cancer detection, where it demonstrated diagnostic value alongside TTC3 and EPCAM 3. The clinical significance of this finding requires further investigation to distinguish its role in cancer biology from its primary histone function.