Estimates of the overall numbers of variants with different sequence consequences are comparable to previous values 1,20-22 (Table S14). However, only a fraction of these are likely to be functionally-relevant. A more accurate picture of the number of functional variants is given by the number of variants segregating either at conserved positions (here defined as sites with a GERP19 conservation score of >2), or where the function (e.g., STOP gain) is strong and independent of conservation (Table 2). We find that individuals typically carry over 2,500 nonsynonymous variants at conserved positions, 20-40 variants identified as damaging24 at conserved sites and about 150 loss-of-function variants (LOF: STOP gains, frameshift indels in coding sequence and disruptions to essential splice-sites). However, most of these are common (>5%) or low-frequency (0.5-5%) such that the numbers of rare (<0.5%) variants in these categories (which might be considered as pathological candidates) are much lower; 130-400 nonsynonymous variants per individual, 10-20 LOF variants, 2-5 damaging mutations and 1-2 variants identified previously from cancer genome sequencing25. By comparison to synonymous variants, we can estimate the excess of rare
