Provided are methods and systems for determining the clinical significance of a genetic variant. The methods entail determining, for the variant, (a) a function score based on known impact of the variant on a biological function of a cell or protein, (b) a frequency score based on the frequency of the variant in a population, (c) a co-occurrence score based on how the variant co-occurs with a reference variant having known clinical significance relating to a clinical disease or condition, and (d) a family segregation score based on how the variant segregates with a disease or condition in a family; and aggregating, on a computer, the function score, the frequency score, the co-occurrence score, the family segregation score to generate a clinical significance score indicating the clinical significance of the genetic variant.