A prior investigation of these SHP-1 variants at pH 5.0 in a medium containing 40% glycerol observed faster rates than the WT enzyme, which were hypothesized to arise from enhanced WPD-loop dynamics. This study shows the variants do not have broadly faster rates in aqueous solution, but their pH dependencies have been altered and, as a result, some of the variants exhibit faster turnover than WT at pH >6, reflected in a higher kinetic pKa of the catalytic residue D421. Further, our molecular dynamics simulations indicate that there are no statistically significant differences in loop dynamics, and any differences in pKa of the aspartic acid likely arise from differences in solvation of this side chain in the SHP-1 variants. The modeling results and structural analysis thus far suggest that the origins of shifted pH dependencies among these SHP-1 variants results primarily from changes in solvation and hydrogen-bonding networks that affect the pKa of the D421 residue. This explains why the changes in pH-rate profiles for kcat in these variants are observed on the basic limb. These findings contrast with the observations from mutations in YopH and PTP1B, whose pH dependencies for kcat were more broadly affected on both acidic and basic limbs. In summary, the results here combined with our previous work show multiple avenues exist by which mutations to noncatalytic residues affect the pH dependency of catalysis in PTPs. This phenomenon provides a means for nature to tune the activity of enzymes in particular environments, and for point mutations to alter an enzyme's activity in pH-dependent cellular processes, potentially with pathogenic consequences. The findings also emphasize the need to characterize the catalytic effect of enzyme mutations beyond comparative kinetic measurements at a single pH.