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Introduction: Hereditary spherocytosis (HS) is a common hereditary hemolytic anemia characterized by chronic hemolysis, increased indirect serum bilirubin, the presence of reticulocytes and spherocytes in blood smears, and great heterogeneity at the clinical, biochemical, and molecular levels. The molecular pathology of HS includes genetic variants at five genes: ANK1 , EPB42 , SLC4A1 , SPTA1 , and SPTB . Alpha spectrin ( SPTA1 ) deficiency is the second leading cause of HS in Mexican patients. Aim: To assess the effects of five SPTA1 variants on the hematological phenotype of Mexican patients with HS. Materials and Methods: This study included a retrospective cohort of 227 biologically unrelated patients with HS. Variants c.4339-99C>T and c.6531-12C>T in SPTA1 were identified by the amplification-refractory mutation system polymerase chain reaction (ARMS-PCR), and variants c.5572C>T, c.5992C>G, and c.6794T>C were identified by quantitive Real Time-Polymerase Chain Reaction (qRT-PCR) allelic discrimination. Risk tests were performed for each variant with respect to HS clinical severity. Results: The SPTA1 c.5992C>G variant showed association with moderately severe HS ( p  = 0.006, odds ratio = 5.67, confidence interval 95%  = 1.6-19.9); the risk increased when the variant was in compound heterozygosity with α LELY and c.6794T>C. Lower hematological levels were observed in simple α Lely (c.5572C>T and c.6531-12C>T), and c.5992C>G heterozygotes (red blood cell [RBC] p  = 0.028 and 0.010; hemoglobin [Hb] p  = 0.030 and 0.002; packed cell volume [PCV] p  = 0.034 and 0.002 respectively), and in c.5992C>G+c.6794T>C compound heterozygotes (RBC p  = 0.043; Hb p  = 0.033; PCV p  = 0.043). Additional genetic traits were observed: 15% had HS+Gilbert syndrome and 13% HS+thalassemia. Conclusion: Although most of the studied variants are considered benign, we observed significant associations with phenotypic severity. Therefore, we recommend the inclusion of these variants in molecular screening for HS.