The 6 individual FVIII domain structures and their 2863 missense variants. The 6 structures were taken from the AlphaFold prediction. All 6 regions are shown as ribbon diagrams in rainbow colors from the N terminus (blue) to the C terminus (red). The structurally similar A1, A2, and A3 domains are shown with their secondary structure ribbons depicted in the same orientations and, similarly, the structurally similar C1 and C2 domains. The black spheres denote the missense mutations in each domain (A1, 629 variants; A2, 621 variants; A3, 537 variants; B, 483 variants; C1, 241 variants; C2, 235 variants). These variants total 2746, and the remaining 117 variants occur in the a1 linker (29 variants), the a2 linker (19 variants), the a3 linker (39 variants) and the signal peptide (29 variants). A further 1 variant was reported without information on its location. Note that the modeled structure of the B domain was predicted from AlphaFold with very low confidence and should not be overinterpreted to assume it actually surrounds the A and C domains as pictured.