Location of hemophilia A–associated missense mutations across the r-fVIII structure. (A) The disease phenotype/symptom designations of “mild,” “moderate,” and “severe” are taken from the HamSters database⁴⁸  and correspond to plasma fVIIIa activity levels of 6% to 30%, 1% to 5% and less than 1%, respectively. (B) The presence of mutations in the interfaces of the C domains with each other and with the A3 domain.