Structural and schematic views of variants within the FVIII domains. (A) The AlphaFold model for full-length FVIII is shown in ribbon format. The structure is shown in rainbow colors, starting with blue at the N terminus (N) and ending with red at the C terminus (C). The disordered B domain is depicted as a ribbon encompassing the A and C domains, although its predicted conformation is of very low confidence. (B) The FVIII structure from panel A is shown schematically in cartoon form in the same orientation and colors. The globular A1, A2, A3, C1, and C2 domains are denoted by filled circles. The disordered B domain is schematically represented by a green line. (C) The 2863 missense variants are mapped to the ribbon diagram, in which the occurrence of multiple different variants with mild, moderate, and severe phenotypes are shown as colored spheres. The mild, moderate, and severe variants are overlaid onto the ribbon diagram of panel C. (D) The 2863 missense variants are mapped to the ribbon diagram, in which the phenotype classifications of mild, moderate, and severe effects are denoted as the traffic light colors green, yellow, and red, respectively. (E) The 25 most commonly reported synonymous variants are shown as spheres in the ribbon structure of FVIII shown in panel A. Black spheres denote the 5th to 25th most common variants, and the 4 labeled magenta spheres denote the top 4 most common synonymous variants seen in FVIII.