Canonical methods of protein evolution include diversification of folds through genetic and epigenetic alterations including point mutations, silencing, deletions and duplication. Following a survey of the entire human mutation database, we describe a new mechanism ‘structural capacitance’ that enables the de novo generation over rapid timescales of new peptide microstructures in previously disordered regions. These new elements of peptide microstructure are functionally implicated in the pathogenesis of a wide range of human diseases. The finding has implications for the ancestral diversification of protein folds, the engineering of highly evolvable proteins, and the identification and selective targeting of human disease epitopes.