The question addressed in this report focuses on the autoantigenicity of self antigens, principally cytochrome c and lysozyme. Of interest is whether the immune system produces autoantibodies to its host proteins reacting randomly with all potential antigen sites or is autoreactively selective for certain determinants. Based on experimental evidence from autoantibodies against cytochromes c, Jemmerson and Margoliash [Jemmerson, R. & Margoliash, E. (1979) Nature (London) 282, 468-471] have described a striking correlation between autoreactive sequence regions and evolutionary instability. While their analysis of evolutionary variation was based on simple sequence variability plots, we present here a refined approach that takes into account the distinction between evolutionary substitutions that induce a change in the protein surface from those that do not (surface-neutral substitutions). A quantitative aspect of surface variation (surface consensus) is included in the algorithm that produces a ranked order for autoantigenic determinants. The final plot, called surface variability, indicates sequence regions having a preference for autoimmune reaction. We propose the term "autogen" to designate such protein determinants.