From early detection of variants of concern to vaccine and therapeutic design, pandemic preparedness depends on identifying viral mutations that escape the response of the host immune system. While experimental scans are useful for quantifying escape potential, they remain laborious and impractical for exploring the combinatorial space of mutations. Here we introduce a biologically grounded model to quantify the viral escape potential of mutations at scale. Our method - EVEscape - brings together fitness predictions from evolutionary models, structure-based features that assess antibody binding potential, and distances between mutated and wild-type residues. Unlike other models that predict variants of concern based on newly observed variants, EVEscape has no reliance on recent community prevalence, and is applicable before surveillance sequencing or experimental scans are broadly available. We validate EVEscape predictions against experimental data on H1N1, HIV and SARS-CoV-2, including data on immune escape. For SARS-CoV-2, we show that EVEscape anticipates mutation frequency, strain prevalence, and escape mutations. Drawing from GISAID, we provide continually updated escape predictions for all current strains of SARS-CoV-2.Competing Interest StatementD.S.M. is an advisor for Dyno Therapeutics, Octant, Jura Bio, Tectonic Therapeutic and Genentech, and is a co-founder of Seismic Therapeutic.