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The diseases present with a broad range of phenotypes including lethality, severe neurological manifestations, seizures, and intellectual disability. However, because L\u2010serine supplementation, especially if started prenatally, can ameliorate and in some cases even prevent symptoms, knowledge of pathogenic variants is medically actionable. Here, we describe a functional assay that leverages the evolutionary conservation of an enzyme in the serine biosynthesis pathway, phosphoserine aminotransferase, and the ability of the human protein\u2010coding sequence (<jats:italic>PSAT1<\/jats:italic>) to functionally replace its yeast ortholog (<jats:italic>SER1<\/jats:italic>). Results from our quantitative, yeast\u2010based assay agree well with clinical annotations and expectations based on the disease literature. Using this assay, we have measured the functional impact of the 199 <jats:italic>PSAT1<\/jats:italic> variants currently listed in ClinVar, gnomAD, and the literature. We anticipate that the assay could be used to comprehensively assess the functional impact of all SNP\u2010accessible amino acid substitution mutations in <jats:italic>PSAT1<\/jats:italic>, a resource that could aid variant interpretation and identify potential NLS carriers.<\/jats:p>","DOI":"10.1002\/jimd.12227","type":"journal-article","created":{"date-parts":[[2020,2,20]],"date-time":"2020-02-20T05:30:10Z","timestamp":1582176610000},"page":"758-769","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["A yeast\u2010based complementation assay elucidates the functional impact of 200 missense variants in human <i>PSAT1<\/i>"],"prefix":"10.1002","volume":"43","author":[{"given":"Amy","family":"Sirr","sequence":"first","affiliation":[{"name":"Pacific Northwest Research Institute  Seattle Washington"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Russell 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