A method for determining the clinical significance of a genetic variant, comprising determining, for the variant, (a) a function score based on known impact of the variant on a biological function of a cell or protein, wherein the impact comprises the activity or expression level change of the 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 (e) optionally, a minor evidence score based on information from at least one functional impact prediction algorithm selected from Sorting Intolerant From Tolerant (SIFT) and Polymorphism Phenotyping (PolyPhen), whether the variant occurs within a critical protein domain, whether the variant would alter a post-translational modification, whether other known pathogenic variants occur within the same codon, and whether the variant is known to occur in at least one patient of a disease or condition; and aggregating, on a computer, the function score, the frequency score, the co-occurrence score, and the family segregation score, and optionally the minor evidence score to generate a clinical significance score indicating the clinical significance of the genetic variant, wherein the aggregation comprises summing up the function score, the frequency score, the co-occurrence score, the family segregation score, and optionally the minor evidence score with pre-determined weights, or wherein the aggregation comprises taking the function score, the frequency score, the co-occurrence score, the family segregation score, and optionally the minor evidence score as inputs in a decision tree, each leaf of the decision tree comprising a value for the clinical significance score. (a) a function score based on known impact of the variant on a biological function of a cell or protein, wherein the impact comprises the activity or expression level change of the 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 (e) optionally, a minor evidence score based on information from at least one functional impact prediction algorithm selected from Sorting Intolerant From Tolerant (SIFT) and Polymorphism Phenotyping (PolyPhen), whether the variant occurs within a critical protein domain, whether the variant would alter a post-translational modification, whether other known pathogenic variants occur within the same codon, and whether the variant is known to occur in at least one patient of a disease or condition; and aggregating, on a computer, the function score, the frequency score, the co-occurrence score, and the family segregation score, and optionally the minor evidence score to generate a clinical significance score indicating the clinical significance of the genetic variant, wherein the aggregation comprises summing up the function score, the frequency score, the co-occurrence score, the family segregation score, and optionally the minor evidence score with pre-determined weights, or wherein the aggregation comprises taking the function score, the frequency score, the co-occurrence score, the family segregation score, and optionally the minor evidence score as inputs in a decision tree, each leaf of the decision tree comprising a value for the clinical significance score.