Increasing evidence indicates that genes containing disease causal variation have distinct functional and genomic properties. The importance of understanding these properties is highlighted by efforts to filter lists of variants from next-generation sequencing studies, where the number of potentially deleterious variants, which are in fact unrelated to disease, may be large. Available evidence indicates that the majority of disease genes are non-essential and their products occupy functionally peripheral positions in protein networks. They tend to be intermediate between genes that have core biological functions, particularly low mutation rates and low haplotype diversity, and genes for which high haplotype diversity and high mutation rates are advantageous (such as those involved in sensory perception and some immune system functions). Evidence presented here supports these conclusions through analysis of integrated data sets incorporating the latest mutational profiles, linkage disequilibrium structure and other genomic properties of individual genes. The analysis highlights the contrasting functions of genes predicted as least and most likely to contain disease variation and provides a basis for filtering gene variant lists to exclude the least plausible disease candidates. 