Therefore, it can be speculated that the gain-of-function variant V2R-R137L locks the receptor in a configuration able to directly or indirectly activate a “non-canonical” Gα12/13–Rho–ROCK signaling leading to AQP2 phosphorylation at S/T269 and constitutive increase in the osmotic water permeability which translates into the pathological outcome of NSIAD. This evidence concerns the gene AQP2 and nephrogenic syndrome of inappropriate antidiuresis.