H3F3B encodes H3.3B, a replacement histone variant that differs from replication-dependent histones by being expressed throughout the cell cycle rather than only during DNA replication 1. The gene is located on chromosome 17 as a solitary gene, contrasting with clustered replication-dependent histone genes 1. H3.3B contains characteristic structural features including introns in both the 5' untranslated region and coding sequence, plus polyadenylation signals rather than histone-specific dyad symmetry elements 1. Transcriptionally, H3F3B is regulated by Oct-1, CREB/ATF, and AP-1 transcription factors binding to its proximal promoter 2. The gene shows tissue-specific expression patterns, being primarily expressed in adult tissues while replication-dependent H3.1 is mainly expressed in fetal tissues 3. Clinically, germline variants in H3F3B cause Bryant-Li-Bhoj syndrome, a neurodevelopmental disorder characterized by intellectual disability, craniofacial anomalies, and abnormal neuroimaging 4. Additionally, somatic H3F3B mutations, particularly K36M substitutions, are associated with malignant chondroblastoma, a rare bone tumor with high rates of recurrence and metastasis 5. The gene is also overexpressed in colorectal cancer, suggesting potential utility as a prognostic biomarker 6.