Ultraspecific, programmable nucleic acid sensors capable of detecting and preferentially amplifying target DNA molecules comprising a particular SNP or mutation are provided. In some cases, the ultraspecific programmable nucleic acid sensors are useful for detecting SNP-containing DNA molecules indicative of cancer such as cell-free DNA circulating in the blood or indicative of organ transplant rejection Also provided are methods for construction of such ultraspecific nucleic acid sensors and methods for preferential amplification of target DNA molecules containing a mutation of interest, as well as testing systems for early cancer screening and routine monitoring of circulating cancer DNA using liquid biological samples such as serum, plasma, or saliva.