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Using millions of SARS-CoV-2 full-genome sequences, we estimate rates of synonymous mutations for each mutation type and examine how much these rates vary between sites. We find a surprisingly high level of variability. A substantial fraction of this variability can be explained by local sequence context, genomic region, and RNA secondary structure. We estimate fitness effects of each mutation based on the number of times it actually occurs versus the number of times it is expected to occur based on a model of the above features. We identify small regions of the genome where synonymous or noncoding mutations occur much less often than expected, indicative of strong purifying selection on the RNA sequence independent of protein sequence. Overall, this work expands our basic understanding of SARS-CoV-2\u2019s evolution by characterizing the virus\u2019s mutation process at the level of individual sites and uncovering several striking mutational patterns that arise from unknown mechanisms.<\/jats:p>","DOI":"10.1093\/nar\/gkaf503","type":"journal-article","created":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T07:44:13Z","timestamp":1748504653000},"source":"Crossref","is-referenced-by-count":20,"title":["The mutation rate of SARS-CoV-2 is highly variable between sites and is influenced by sequence context, genomic region, and RNA structure"],"prefix":"10.1093","volume":"53","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8324-8324","authenticated-orcid":false,"given":"Hugh\u00a0K","family":"Haddox","sequence":"first","affiliation":[{"name":"Computational Biology Program, Fred Hutchinson Cancer Research Center , Seattle, WA 98102 ,","place":["United 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