Project Summary The breadth and complexity of human variation is one of the great scientific and medical challenges of our time. Modern sequencing technologies now enable detailed measurements of germline and somatic alterations, many of which underlie human disease. Variants can be characterized by their locations in genomic DNA, evolutionary, physicochemical, structural, and functional properties, as well as by their effects on RNA transcripts, proteins, molecular interactions. Ultimately, we must find new methods to measure quantitatively their impacts on human cells, tissues and lives. To address this fundamental challenge in 2022, this fifth Human Genetic Variation and Disease Gordon Research Conference will bring together leading researchers and clinicians from system biology, genomics, computer science, molecular biology, medical geneticist, population geneticist, data science, biophysics, and experts in health informatics who will discuss over 6 days the interpretation of genetic and genomic variants at the DNA, RNA and protein levels. This edition, however, will significantly expand its clinical scope to ensure the timeliness and importance of the meeting. We will now twin the technical focus on diverse variations typical of this meeting to their explicit impact on the immune system, the COVID pandemic, interactions with the microbiome, proliferative disease and early onset diseases, with each of these conditions being addressed in their own dedicated session. Each session will feature speakers at the frontlines of algorithmic advances to analyze big data who also interpret their results in these specific clinical areas. This will reflect the increasing translational relevance of basic computational biology now that high throughput variant data are being gathered on a massive scale across vast human cohorts (All of Us, the UK biobank, for example) and causing a paradigm shift in each of these clinical themes. This new design will systematically enable timely and critical assessment of the state of the art for variant interpretation in each disease area. Our meeting will be unique in the way it will compare and contrast diverse methods that address different variants in different patient contexts. This will put participants in a privileged position to reassess the current state of the field and guide the future of this expanding field based on careful exposition and critical discussion of evidence.