A previous kinetic study of a set of SHP-1 alanine variants reported higher phosphatase activities than the WT enzyme, speculated to arise from increased WPD-loop flexibility and stability. One of these mutations was to the residue immediately following the general acid D421, and it was speculated that the side chain length of the D+1 residue affected the catalytic rate by altering the dynamic rate of the WPD-loop. There is precedent for a mutation in the D+1 position affecting turnover by altering WPD-loop dynamics. In the D+1 position in PTP1B, the mutation F182Q results in a decrease of about an order of magnitude in kcat with no shift in the pH optimum but a broader maximum than the native enzyme, and retention of the basic limb. Because of the effect on the pH dependency of catalysis in that case, we sought to investigate some of the previously reported SHP-1 variants across a pH range to more broadly examine the effect of the mutations. We collected and compared kinetic data for the catalytic activities of three SHP-1 variants, S418A, H422Q, and E427A, with those of WT-SHP-1. Residues S418 and E427 reside on the N-terminal and the C-terminal hinge of the WPD-loop, respectively, and H422 is the D+1 residue.