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Missense variants, which can alter protein structure, conformation and immunogenicity, are found in nearly all individuals with mild or moderate hemophilia A but in fewer than 20% of those with the severe form. Here, we identified a 26\u2010year\u2010old man with a hemizygous\n                    <jats:italic>F8<\/jats:italic>\n                    mutation (NM_000132.4(F8):c.5399\u2009G\u2009&gt;\u2009A (p. Arg\n                    <jats:sup>1800<\/jats:sup>\n                    His)) through direct sequencing of all exons of the\n                    <jats:italic>F8<\/jats:italic>\n                    gene, which is established to cause a lack of FVIII:c (%) in circulating blood and leads to moderate HA. In addition, we also provide evidence for the reduced active FVIII (FVIII:c (%)) caused by p. Arg\n                    <jats:sup>1800<\/jats:sup>\n                    His mutation. In detail, we show that p. Arg\n                    <jats:sup>1800<\/jats:sup>\n                    His mutation may activate the unfolded protein response through IRE1a\u2010XBP1 pathway and reduce stability of FVIII. Results from co\u2010immunoprecipitation assays showed that p. Arg\n                    <jats:sup>1800<\/jats:sup>\n                    His mutation decreases the interaction between FVIII and PDIA5. Furthermore, unbiased molecular dynamics simulations highlight the importance of Arg1800 in the interactions FVIII and von Willebrand factor. These findings demonstrate the crucial role of Arg1800 in the correct biogenesis of FVIII and shed light on molecular mechanisms through which missense mutations in FVIII contribute to the development of moderate hemophilia A.\n                  <\/jats:p>","DOI":"10.1002\/cbin.70164","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T13:45:15Z","timestamp":1778766315000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The p. Arg\n                    <sup>1800<\/sup>\n                    His Mutation of Factor VIII Results in Moderate Hemophilia A Due to Defective Processing and Stability of Functional Protein"],"prefix":"10.1002","volume":"50","author":[{"given":"Han","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Blood Transfusion The First Hospital of Lanzhou University Lanzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiaqi","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics School of Medical Informatics, Xuzhou Medical University Xuzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine The Second Affiliated Hospital of Xi'an Jiaotong University Xi'an 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Neck Surgery Lanzhou University Second Hospital Lanzhou China"},{"name":"Department of Cardiology Yantai Yuhuangding Hospital Yantai 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