Genetic variation in interferon-induced transmembrane protein 3 (IFITM3) contributes to inter-individual differences in influenza outcome, yet a comprehensive functional map of IFITM3 variation remains unavailable. Here we show a high-resolution functional atlas of 2,898 IFITM3 variants across three influenza A strains using deep mutational scanning. Our data reveals a functionally constrained central region, providing functional evidence consistent with a Type II membrane topology and highlighting structural features associated with antiviral activity. Comparison with AlphaMissense reveals systematic limitations in predicting the effects of variants within unstructured N-terminal motifs and lipid-embedded domains. Crucially, computational models fail to recognize variants with enhanced antiviral activity, such as G133Q. By integrating this atlas with ClinVar and gnomAD, we provide a functional readout for rare human alleles that may influence susceptibility to infection. These findings provide a resource for interpreting human variation and establish a framework for studying host-directed antiviral mechanisms.