Amyotrophic Lateral Sclerosis (ALS) is a progressive nervous system disease that affects nerve cells in the brain and spinal cord, causing loss of muscle control and eventually death. Both genetic determinants and environmental triggers are thought to be involved in the development of such disease, but our knowledge of how these factors contribute to the etiology of ALS is extremely limited. Through the establishment of a collaboration with the Project MinE Consortium (https://www.projectmine.com), the Lindblad-Toh Lab at Uppsala University will receive quality-controlled whole genome sequencing (WGS) data from around 7,000 individuals (approximately 4,000 ALS patients and 3,000 control-individuals). We expect this very large cohort to be enriched for both disease-associated deleterious and functionally-relevant regulatory variants, thus representing the ideal dataset for genetic mapping studies. The plan is to explore whether the Zoonomia Project’s high-resolution evolutionary constraint estimates derived from the alignments of 241 mammalian species (1) can be utilized as a predictive tool to discern disease phenotypes from non-disease phenotypes, as well as to stratify the former into relevant disease subgroups. With this project we will a) explore the predictive value of the mammalian evolutionary constraint in the context of human disease and 2) evaluate the power of the mammalian evolutionary constraint as discovery tool and functional potential weighting approach compared to classical genetic association and aggregation methodologies.