• SNP rs1143684 results in either a Phe or Leu at position 47 in human NQO2. • NQO2-L47 has a slightly lower kcat; it also has a lower Ki,app with resveratrol. • NQO2-L47 is more unstable to proteolysis and thermal denaturation. • NQO2-F47 (but not NQO2-L47) shows negative cooperativity towards resveratrol. • NQO2-L47 exists as multiple conformers in solution.