The enzyme VKORC1 reduces vitamin K that functions as a cofactor activating vitamin K–dependent proteins that are critical in coagulation. Czogalla et al show that Arg98 is crucial for proper ER localization of VKORC1, and that the VKCFD2 mutant Arg98Trp causes mistrafficking of VKORC1 from the ER with a concomitant reduction of ∼80% of VKORC1 levels in the ER membrane. Interestingly, tracking the Arg98Trp VKORC1 mutant shows that the protein does not accumulate in the Golgi or plasma membranes. These results highlight, for the first time, a potential mechanism as to why VKCFD2 patients have impaired coagulation capabilities.