Nanogaps functionalized with small diamond-like particles, diamondoids, have been shown to effectively distinguish between different DNA nucleotides. Here, we focus on the detection of mutations and epigenetic markers using such devices. Based on quantum mechanical simulations within the density functional theory approach coupled with the non-equilibrium Green’s function scheme, we provide deeper insight into the inherent differences in detecting modified nucleotides. Our results strongly underline the influence of the type of functionalization molecule of the nanogap, as well its conformational details within the nanogap, on the sensing efficiency of the device. The electronic features for the mutations and epigenetic markers are compared to those for the respective canonical nucleotides that are detected by different devices. The calculations directly correlate the structural and electronic properties of the different nucleotides with the electronic transmission across the diamondoid-based device. The latter was found to be controlled by the functionalizing molecule and its binding to the nucleotides. We report on the direct connection of these characteristics to the sensitivity of the diamondoid-functionalized nanogaps, which could eventually be embedded in a nanopore device, and discuss the implications for DNA sensing.