We need to accurately understand the impacts of protein sequence variants to realize the potential of clinical and cancer genomics for precision medicine, identify how pathogens are adapting to evolutionary pressures, or to learn the fundamental rules that govern biological function at the molecular level. Unfortunately, traditional experimental approaches have lacked the throughput needed to characterize the vast number of protein sequence variants that naturally exist in our world. To address this, we harness mammalian synthetic biology and high throughput DNA sequencing to develop and employ large-scale genetics assays capable of functionally characterizing thousands of protein variants per experiment, across a wide range of biological topics.