Abstract: Activated Protein C (APC) is a vitamin K-dependent anticoagulant plasma serin protease that exerts its action through the inactivation of factors Va and VIIIa in presence of Ca++ and phospholipids. Deficiency of protein C is associated with the risk of developing venous thrombosis. APC shares homologies with other vitamin K-dependent coagulation proteins as a results of a common evolutionary pathway. The chymotrypsin-like serine proteases maintain a strictly conserved active site geometry among their catalytic Ser, His and Asp residues. The fact that this core is highly conserved both in sequence and structure among members of the serine protease family suggests that its shape has been finely tuned during evolution. 33 mutations (18 novel) in the promoter and coding regions of the PC gene were identified by PCR and sequencing in 46 patients reporting venous thromboembolic events. Here we present a computational analysis of three selected mutants (G43E, D194N, G216D) that are localized in the catalytic domain and determine a charge modification in the vicinity of the catalytic triad.