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Despite all the efforts acquired in four years of the COVID-19 pandemic, the path to a full understanding of the biological mechanisms involved in this disease remains complex. This is partly due to a combination of factors, including the inherent characteristics of the infection, socio-environmental elements, and the variations observed within both the viral and the human genomes. Thus, this study aimed to investigate the correlation between genetic host factors and the severity of COVID-19. We conducted whole exome sequencing (WES) of 124 patients, categorized into severe and non-severe groups. From the whole exome sequencing (WES) association analysis, four variants (rs1770731 in CRYBG1, rs7221209 in DNAH17, rs3826295 in DGKE, and rs7913626 in CFAP46) were identified as potentially linked to a protective effect against the clinical severity of COVID-19, which may explain the less severe impact of COVID-19 on the Northern Region. Our findings underscore the importance of carrying out more genomic studies in populations living in the Amazon, one of the most diverse from the point of view of the presence of rare and specific alleles. To our knowledge, this is the first WES study of admixed individuals from the Brazilian Amazon to investigate genomic variants associated with the clinical severity of COVID-19., (© 2024. The Author(s).)