Patterns of Volatility Across the Spike Protein Accurately Predict the Emergence of Mutations within SARS-CoV-2 Lineages.

New variants of SARS-CoV-2 continue to emerge in the population. Due to mutations in the spike protein, some variants exhibit partial resistance to therapeutics and to the immunity provided by COVID-19 vaccines. Thus, there is a need for accurate tools to forecast the appearance of new virus forms in the population. Here we show that patterns of amino acid variability across the spike protein accurately predict the mutational patterns that appeared within SARS-CoV-2 lineages with considerable advance warning time. Interestingly, mutation probabilities varied greatly between lineages, most notably for critical sites in the receptor-binding domain of spike. The high predictive capacity of the model allows design of vaccines that address the properties of variants expected to emerge in the future.