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More than 200 variants are associated with enzyme deficiency: each one of them may either cause predisposition to haemolytic anaemia triggered by exogenous agents (class B variants), or may cause a chronic haemolytic disorder (class A variants). Genotype\u2013phenotype correlations are subtle. We report a rare <jats:italic>G6PD<\/jats:italic> variant, discovered in a baby presenting with severe jaundice and haemolytic anaemia since birth: the mutation of this class A variant was found to be p.(Arg454Pro). Two variants affecting the same codon were already known: <jats:italic>G6PD Union<\/jats:italic>, p.(Arg454Cys), and <jats:italic>G6PD Andalus<\/jats:italic>, p.(Arg454His). Both these class B variants and our class A variant exhibit severe G6PD deficiency. By molecular dynamics simulations, we performed a comparative analysis of the three mutants and of the wild\u2010type G6PD. We found that the tetrameric structure of the enzyme is not perturbed in any of the variants; instead, loss of the positively charged Arg residue causes marked variant\u2010specific rearrangement of hydrogen bonds, and it influences interactions with the substrates G6P and NADP. These findings explain severe deficiency of enzyme activity and may account for p.(Arg454Pro) expressing a more severe clinical phenotype.<\/jats:p>","DOI":"10.1111\/bjh.19775","type":"journal-article","created":{"date-parts":[[2024,9,19]],"date-time":"2024-09-19T02:14:33Z","timestamp":1726712073000},"page":"1985-1994","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Pathogenic <i>G6PD<\/i> variants: Different clinical pictures arise from different missense mutations in the same codon"],"prefix":"10.1111","volume":"205","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0980-5297","authenticated-orcid":false,"given":"Simonetta","family":"Costa","sequence":"first","affiliation":[{"name":"Dipartimento di Scienze della Salute della Donna, del Bambino e di Sanit\u00e0 Pubblica Fondazione Policlinico Universitario Agostino Gemelli IRCCS  Rome Italy"},{"name":"Dipartimento di Scienze della Vita e Sanit\u00e0 Pubblica Universit\u00e0 Cattolica del Sacro Cuore  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelo","family":"Minucci","sequence":"additional","affiliation":[{"name":"Molecular and Genomic Diagnostics Unit Fondazione Policlinico Universitario A. 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