AbstractBackgroundAlpha 1‐antitrypsin (A1AT) deficiency is related to lung and liver diseases, including pulmonary emphysema and liver cirrhosis in humans. Genetic variations including single nucleotide polymorphisms (SNPs) of SERPINA1 are responsible for A1AT deficiency, but the characteristics of the SNPs are not well‐understood. Here, we investigated the features of a rare SNP (F51S) of A1AT, which introduces an additional N‐glycosylation site in the N‐terminal region of A1AT.MethodsWe evaluated the F51S variant compared with the wild‐type (WT) A1AT with regard to expression in CHO‐K1 cells, trypsin inhibitory activity, polymerization, and thermal stability.ResultsThe recombinant F51S protein expressed in CHO‐K1 cells was mostly retained inside cells. The F51S variant had trypsin inhibitory activity, but reduced thermal stability compared with the WT A1AT. The native acrylamide gel data showed that F51S tended to prevent polymerization of A1AT.ConclusionThe results of this study indicate that Phe51 and the surrounding hydrophobic residue cluster plays an important role in the conformation and secretion of A1AT and suggest the harmful effects of a rare F51S SNP in human health.