We found a 6–8-fold elevated risk for venous thromboembolism among patients with protein S deficiency, and furthermore discovered a mutation hotspot around exons 11 and 12 of PROS1. These findings are conducive to the clinical application of protein S assays for the molecular diagnosis of thrombophilia. This evidence concerns the gene PROS1 and hyperinsulinemic hypoglycemia, familial, 4.