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VKOR is also the target of the widely used anticoagulant drug, warfarin. Despite VKOR\u2019s pivotal role in coagulation, its structure and active site remain poorly understood. In addition, VKOR variants can cause vitamin K-dependent clotting factor deficiency or alter warfarin response. Here, we used multiplexed, sequencing-based assays to measure the effects of 2,695 VKOR missense variants on abundance and 697 variants on activity in cultured human cells. The large-scale functional data, along with an evolutionary coupling analysis, supports a four transmembrane domain topology, with variants in transmembrane domains exhibiting strongly deleterious effects on abundance and activity. Functionally constrained regions of the protein define the active site, and we find that, of four conserved cysteines putatively critical for function, only three are absolutely required. Finally, 25% of human VKOR missense variants show reduced abundance or activity, possibly conferring warfarin sensitivity or causing disease.<\/jats:p>","DOI":"10.7554\/elife.58026","type":"journal-article","created":{"date-parts":[[2020,9,1]],"date-time":"2020-09-01T09:01:29Z","timestamp":1598950889000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.58026","source":"Crossref","is-referenced-by-count":99,"title":["Multiplexed measurement of variant abundance and activity reveals VKOR topology, active site and human variant impact"],"prefix":"10.7554","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1880-3181","authenticated-orcid":true,"given":"Melissa A","family":"Chiasson","sequence":"first","affiliation":[{"name":"Department of Genome Sciences, University of Washington, Seattle, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan J","family":"Rollins","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, Harvard Medical School, Boston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason J","family":"Stephany","sequence":"additional","affiliation":[{"name":"Department of Genome Sciences, University of Washington, Seattle, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine A","family":"Sitko","sequence":"additional","affiliation":[{"name":"Department of Genome Sciences, University of Washington, Seattle, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth A","family":"Matreyek","sequence":"additional","affiliation":[{"name":"Department of Genome Sciences, University of Washington, Seattle, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Verby","sequence":"additional","affiliation":[{"name":"Donnelly Centre and Departments of Molecular Genetics and Computer Science, University of Toronto, and Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Sun","sequence":"additional","affiliation":[{"name":"Donnelly Centre and Departments of Molecular Genetics and Computer Science, University of Toronto, and Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick P","family":"Roth","sequence":"additional","affiliation":[{"name":"Donnelly Centre and Departments of Molecular Genetics and Computer Science, University of Toronto, and Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"DeSloover","sequence":"additional","affiliation":[{"name":"Color Genomics, Burlingame, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9388-2281","authenticated-orcid":true,"given":"Debora S","family":"Marks","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, Harvard Medical School, Boston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allan E","family":"Rettie","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, University of Washington, Seattle, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7614-1713","authenticated-orcid":true,"given":"Douglas M","family":"Fowler","sequence":"additional","affiliation":[{"name":"Department of Genome Sciences, University of Washington, Seattle, United States"},{"name":"Department of Bioengineering, University of Washington, Seattle, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2020,9,1]]},"reference":[{"key":"bib1","article-title":"VKOR abundance and activity score analysis","volume-title":"GitHub","author":"Chiasson","year":"2020","unstructured":"Chiasson MA. 2020a. 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