An ultrasensitive electrochemical sensor has been constructed for the detection of single nucleotide polymorphisms (SNPs) based on DNA-functionalized Cd-MOFs-74 as cascade signal amplification probe under enzyme-free conditions. Interestingly, the introduction of an auxiliary probe did not disturb the detection of SNP targets, but could bind more Cd-MOFs-74 signal elements to enhance the different pulse voltammetry electrochemical signal 2~3 times as compared to sensing system without auxiliary probe, which obviously improves the sensitivity of the proposed sensor. Experimental results taking p53 tumor suppressor gene as SNP model demonstrated that the proposed method can be employed to sensitively and selectively detect target p53 gene fragment with a linear response ranging from 0.01 to 30 pmol/L (detection limit of 6.3 fmol/L) under enzyme-free conditions. Utilizing this strategy, the ultrasensitive SNP electrochemical sensor is a promising tool for the determination  of SNPs in biomedicine. Graphical Abstract.