The plasma level of chromogranin A (CgA) is elevated in genetic hypertension. Conversely, plasma level of the CgA peptide catestatin is diminished in individuals with established hypertension and those with a genetic risk for this disease. Resequencing of the human CHGA gene identified three naturally occurring variants of catestatin (Gly364Ser, Pro370Leu, Arg374Gln) that exhibit different potencies in inhibiting catecholamine secretion. Here we have examined whether there is any differential processing of the three CHGA variants to catestatin by the endoproteolytic enzyme plasmin. Plasmin digestion of the purified CgA proteins generated a stable biologically active 14-amino acid peptide (hCgA_360-373) from the wild-type, Gly364Ser and Arg374Gln proteins despite the disruption of the dibasic site (Arg₃₇₃Arg₃₇₄) in the Arg374Gln variant. Unexpectedly, the action of plasmin in generating the catestatin peptide from the Pro370Leu protein was less efficient. The efficiency of cleavage at the dibasic Arg₃₇₃Arg₃₇₄ site in synthetic human CgA_360-380 was 3- to 4-fold less in Pro370Leu CgA, compared to the wild-type. Circular dichroism of the synthetic CgA_352–372 suggested a difference in the amount of -helix and -sheet between the wild-type and Pro370Leu CgA peptides. As the Pro₃₇₀ residue is in the P4 position, the local secondary structure in the vicinity of the cleavage site may enforce the specificity or accessibility to plasmin. The less efficient proteolytic processing of the Pro370Leu protein by plasmin, coupled with the strong association of this variant with ethnicity, suggests the Pro370Leu CHGA gene variant may contribute to the differential prevalence of cardiovascular disease across ethnic groups.