The Human Oral and Craniofacial Atlas of Health and Disease

Oral and craniofacial diseases span interconnected epithelial, glandular, stromal, immune, vascular, neural and mineralized-tissue niches, yet single-cell resources remain fragmented by tissue and disease. Here we establish the Human Oral and Craniofacial Atlas (HOCA), integrating 2.2 million quality-controlled cells from 365 donors across anatomical regions and 18 oral disease conditions. By fixing both anatomical position and cell-state identity in one coordinate system, HOCA reframes oral disease not as site-specific pathology or a generic inflammatory response, but as anatomically anchored recombinations of a shared, finite set of cell states. The healthy reference of 0.68 million cells resolves 139 cell types and states, delineating regionalized cellular programmes, recovering rare oral Merkel cells and defining gingiva-enriched basal-interface fibroblast states. Projecting 18 disease conditions onto this reference shows that each is defined by a distinct combination of shared states rather than unique lineages, with a recurrent SPARC+ pericyte fibrovascular node and a CD8 T-cell axis that stratifies disease by transcriptional state rather than abundance. We developed ORACLE (Oral Reference Atlas for Cell Learning and Embedding), a reference-mapping tool transferring HOCA identities to new datasets. The reference and ORACLE are openly available, providing an anatomy-aware coordinate system for oral and craniofacial health and disease.