BackgroundThe use of molecular biomarkers for COVID-19 remains unconclusive. The application of a molecular biomarker in combination with clinical ones that could help classifying aggressive patients in first steps of the disease could help clinician and sanitary system a better management of the disease. Here we characterize the role ofACE2, AR, MX1, ERG, ETV5andTMPRSS2for trying a better classification of COVID-19 through knowledge of the disease mechanisms.MethodsA total of 329 blood samples were genotyped inACE2,MX1andTMPRSS2. RNA analyses were also performed from 258 available samples using quantitative polymerase chain reaction for genes:ERG, ETV5, AR, MX1, ACE2,andTMPRSS2.Moreover, in silico analysis variant effect predictor, ClinVar, IPA, DAVID, GTEx, STRING and miRDB database was also performed. Clinical and demographic data were recruited from all participants following WHO classification criteria.ResultsWe confirm the use of ferritin (p< 0.001), D-dimer (p< 0.010), CRP (p< 0.001) and LDH (p< 0.001) as markers for distinguishing mild and severe cohorts. Expression studies showed thatMX1andARare significantly higher expressed in mild vs severe patients (p< 0.05).ACE2andTMPRSS2are involved in the same molecular process of membrane fusion (p= 4.4 × 10–3), acting as proteases (p= 0.047).ConclusionsIn addition to the key role ofTMPSRSS2, we reported for the first time that higher expression levels ofARare related with a decreased risk of severe COVID-19 disease in females. Moreover, functional analysis demonstrates thatACE2, MX1andTMPRSS2are relevant markers in this disease.Graphical abstractSupplementary InformationThe online version contains supplementary material available at 10.1186/s40246-023-00496-2.