It remains a challenge to synthesize Au@Ag nanocubes in an aqueous system with sharp corners, edges and tunable aspect ratio in the past decade. Here, sharp-featured Au@Ag core/shell nanocuboids have been successfully synthesized in the aqueous system with tunable aspect ratio from 1 to 3. By chaging the solvent polarity, the assembly structure can be tuned from micrometer order 2D structure with different surface roughness to 3D structure. In addition, simulation and experimental results demonstrated that the sharp feature and in-cuboid, out-of-cuboid LSPR coupling of Au@Ag core/shell nanocuboids enabled high SERS activities. The ultrasensitive detection of single-point mutations of TDP-43 and IAPP8-37 proteins was demonstrated at 10 pM for the first time. This could be a general strategy for the single-point mutation detection of proteins.