Secondary structure and accessibility analysis of variants occurring in the FVIII protein. The FVIII amino acid sequence is shown with secondary structure assignments and solvent accessibilities indicated below each residue. Secondary structures are assigned as H (α-helix), B (β-bridge), E (extended β-strand), G (3₁₀ helix), I (π-helix), T (hydrogen-bonded turn), S (bend), or C (undefined coil region). These were determined from the FVIII crystal structure when the residues were visible and present (PDB ID 6MF2). Sequences within this crystal structure are shown in black, and sequences without a crystal structure are shown in blue. For the latter, secondary structure and solvent accessibility predictions were made based on the modeled FVIII AlphaFold structure. The positions of 4243-point variants that occur in the F8 exons are highlighted in yellow, green, and red. These include point missense, point nonsense, and point silent variants. Yellow denotes point variants that occur in ≤4 patients, green denotes point variants that occur in ≥5 patients, and red denotes point variants that occur in >50 patients. Posttranscriptional modifications are shown. These include 25 putative N-glycan sites (highlighted in cyan), 8 numbered Cys-Cys disulfide bridges (highlighted in blue), and 6 sulfated numbered Tyr residues (highlighted in gray).