Immunologic research has revealed extensive mechanistic information about the cellular and macromolecular components of the immune system. Mono- and polygenic disorders causing autoimmune and immunodeficiency disease affect these very components. However, the functional consequences of causative genetic variants, both rare mutations (monogenic disorders) and common SNPs (polygenetic diseases) are regularly not known. An asymmetry between our ability to identify variants versus our ability to functionally characterize them produces these mysterious variants of "unknown significance", hampering investigation into monogenetic clinical decision making and polygenetic disease etiology. We present a pipeline combining CRISPR/Cas9 primary human immune cell editing with classical immunologic phenotypic assays to functionally characterize putative causative variants in primary immune cells on an accelerated time scale. As a demonstration in monogenic disorders, we introduce patient mutations in IL2RA and CTLA4 into healthy donor cells and recapitulate the patient's ex vivo functional deficients. Expanding to common SNPs, we discover a novel functional deficit in cells carrying a SNP associated with Crohn's disease, but protective for Type 1 Diabetes. Overall we describe a rapid method for removing "unknown significance" labels from variants in clinical diagnostics and basic research that represents a powerful personalized diagnostic.