Background: Variants within factor VIII (F8) are associated with sex-linked hemophilia A and thrombosis, with gene therapy approaches being available for pathogenic variants. Many variants within F8 remain variants of uncertain significance (VUS) or are under-explored as to their connections to phenotypic outcomes. Methods: We assessed data on F8 expression while screening the UniProt, ClinVar, Geno2MP, and gnomAD databases for F8 missense variants; these collectively represent the sequencing of more than a million individuals. Results: For the two F8 isoforms coding for different protein lengths (2351 and 216 amino acids), we observed noncoding variants influencing expression which are also associated with thrombosis risk, with uncertainty as to differences in females and males. Variant analysis identified a severe stratification of potential annotation issues for missense variants in subjects of non-European ancestry, suggesting a need for further defining the genetics of diverse populations. Additionally, few heterozygous female carriers of known pathogenic variants have sufficiently confident phenotyping data, leaving researchers unable to determine subtle, less defined phenotypes. Using structure movement correlations to known pathogenic variants for the VUS, we determined seven clusters of likely pathogenic variants based on screening work. Conclusions: This work highlights the need to define missense variants, especially those for VUS and from subjects of non-European ancestry, as well as the roles of these variants in women’s physiology.