Objective To report a family with Hailey-Hailey disease (HHD) and to analyze the ATP2C1 gene mutation. Methods The general data of HHD family members were collected for clinical investigation, and the family tree was drawn. ATP2C1 gene was detected by PCR and Sanger direct sequencing in 4 HHD patients of the family, and 3 healthy members in the family and 100 unrelated normal volunteers were taken as controls. Results In the 4 HHD patients, a novel missense mutation (c.472G>A) on the 21^th exon of the ATP2C1 gene was identified, which resulted in a missense mutation of aspartic acid (p.Asp158Asn). But the mutation was not found in the healthy members in the family or the unrelated normal individuals. Conclusion The missense mutation c.472G>A on exon 21 of ATP2C1 gene is a new mutation site, which may be the main cause of HHD.