AbstractIt is nowadays clear that the single base substitutions that occur in the human genome, of which some lead to pathogenic conditions, are non-random and influenced by their flanking nucleobase sequences. However, despite recent progress, the understanding of these “non-local” effects is still far from being achieved. In order to advance this problem, we analyzed the relationship between the base mutability in gene regions and the electron hole transport along the DNA base stacks, as it is one of the mechanisms that have been suggested to contribute to these effects. More precisely, we studied the connection between the observed frequency of single base substitutions and the vertical ionization potential of the base and its flanking sequence, estimated using MP2/6-31G* ab initio quantum chemistry calculations. We found a good correlation between the two quantities, whose sign depend on whether SBS is in an exon, an intron or an untranslated region. Interestingly, the correlation appears to be higher for synonymous than for missense mutations, and when considering the flanking sequence of the substituted base in the 3’ rather than in the 5’ direction. A weaker but still statistically significant correlation it found between the ionization potentials and the pathogenicity of the base substitutions. Moreover, pathogenicity is also preferentially associated with larger changes in ionization potentials upon base substitution. With this analysis we gained new insights into the complex biophysical mechanisms that are at the basis of mutagenesis and pathogenicity, and supported the role of electron-hole transport in these matters.