Loss of function mutations in PHGDH, PSAT1, and PSPH cause a set of rare, autosomal recessive diseases known as Neu-Laxova syndrome (NLS) or serine-deficiency disorders. The diseases present with a broad range of phenotypes, including lethality, severe neurological manifestations, seizures, and intellectual disability. However, because L-serine supplementation, especially if started early in pregnancy, can ameliorate and in some cases even prevent symptoms, knowledge of pathogenic variants is highly actionable. Recently, our laboratory established a yeast-based assay for human PSAT1 function. We have now applied it at scale to assay the functional impact of 1,914 SNV-accessible amino acid substitutions. Our results agree well with clinical interpretations and protein structure-function relationships, supporting the use of our data as functional evidence under the ACMG interpretation guidelines. In addition to assaying the functional impact of individual variants in yeast haploid cells, we can assay pairwise combinations of PSAT1 alleles that recapitulate human genotypes, including compound heterozygotes, in yeast diploids. Results from this diploid assay successfully distinguish patient genotypes from those of healthy carriers and agree well with disease severity. Finally, we present a linear model that can accurately predict biallelic function in diploids using information from the individual allele measurements in haploids. Taken together, our work provides an example of how large-scale functional assays in model systems can be powerfully applied to the study of a rare disease.