COVID took over the world starting in 2020. Everyone quickly “knew” about the novel coronavirus, but how much do they actually know about the virus behind COVID-19? This classroom activity gives students real-world practice in evaluating actual genetic sequences from SARS-CoV-2 and working with genome alignments to identify mutations and cluster different emergence patterns. This activity works through alignments, mutations/variants, protein folding, structure and function, and medical/ immunology implications of the different variants. There are seven parts to this activity, and each one can be incorporated alone into a lesson or collectively used for a lab, case study, or other supplemental activity to strengthen learning objectives in genetics, biology, immunology, and public health. This learning activity is scalable to different levels and has successfully been incorporated into K–12 education as well as college and graduate education.