The inherited bleeding disorder FV deficiency and clotting disorder FV Leiden are caused by genetic variants in the F5 gene. Both diseases occur with mild, moderate, severe, or asymptomatic phenotypes, and either dysfunctional or reduced amounts of plasma FV protein. Here we present an interactive web database containing 363 disease-associated unique F5 variants derived from 801 patient records that rationalizes their occurrence based on the 2224 residue sequence and new FV structures. The 363 variants correspond to 38 (10.5%) mild, 14 (3.9%) moderate, 52 (14.3%) severe, 49 (13.5%) asymptomatic, and 210 (57.8%) unreported phenotypes. The variant distribution in the FV domains A1, A2, A3, B, C1 and C2 was 42 (11.9%), 61 (17.2%), 58 (16.4%), 103 (29.1%), 28 (7.9%) and 29 variants (8.2%) respectively. Both the globular (A1-A3, C1, C2) and disordered (B) regions contain similar proportions of variants. Variants associated with either FV deficiency or FV Leiden do not cluster near known protein-partner binding sites, thus the molecular mechanism leading to their phenotypes cannot be explained. However, the widespread distribution of FV variants in combination with a high proportion of buried variant residues indicated that FV is susceptible to disruption by small perturbations in its globular structure. Variants located in the disordered B domain also appear to disrupt the FV structure. We discuss how the interactive database provides an online resource that clarifies the clinical understanding of FV-associated disorders
