PROJECT SUMMARY (Overall: Human Pangenome Coordination Center) The human reference genome has been the cornerstone of human genetics and genomics research for over twenty years. However, there is a broad consensus that no single reference sequence can fully represent the spectrum of genomic diversity across global populations. Advances in sequencing technologies and a greater appreciation for the importance of genetic diversity make improving the human reference sequence both timely and practical. With advances in long-read sequencing technologies and computational methods, it is now feasible to construct a human pangenome reference that captures and represents the full compendium of genetic variation from a large collection of diverse genomes. We will extend the successful infrastructure developed by the Human Pangenome Reference Consortium Coordination Center. In the next phase, we will significantly improve the human pangenome reference by representing as much human genetic variation as needed to meet disparate scientific and clinical applications, while engaging with international partners and the global research community to provide a widely accessible and user friendly pangenomic resource and tool ecosystem. During the second phase of the Human Pangenome Reference Consortium, our Coordination Center will: i) Continue to maintain and improve the pangenome reference, including supporting the generation of additional diverse, reference quality sequence assemblies; ii) Facilitate adoption of the pangenome reference by the broad research and clinical genetics and genomics communities; iii) Foster the development and deployment of user-friendly informatics tools for the pangenome; iv) Facilitate embedded ELSI research; and, v) Develop international partnerships to ensure that the human pangenome reference engages with the populations it seeks to represent.