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One solution to this \u2018missing heritability problem\u2019 may be rare missense variants, which are individually scarce but collectively abundant. However, the phenotypic impact of rare variants is under-appreciated as gene function is normally studied in the context of a single \u2018wild-type\u2019 sequence. Here, we explore the impact of naturally occurring missense variants in the human population on the cytosolic antibody receptor TRIM21, using volunteer cells with variant haplotypes, CRISPR gene editing and functional reconstitution. In combination with data from a panel of computational predictors, the results suggest that protein robustness and purifying selection ensure that function is remarkably well-maintained despite coding variation.<\/jats:p>","DOI":"10.7554\/elife.48339","type":"journal-article","created":{"date-parts":[[2019,10,15]],"date-time":"2019-10-15T12:42:24Z","timestamp":1571143344000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.48339","source":"Crossref","is-referenced-by-count":9,"title":["Rare missense variants in the human cytosolic antibody receptor preserve antiviral function"],"prefix":"10.7554","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9802-6019","authenticated-orcid":true,"given":"Jingwei","family":"Zeng","sequence":"first","affiliation":[{"name":"MRC Laboratory of Molecular Biology, Cambridge, United 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