BACKGROUND Mortality remains very high and unpredictable in COVID-19, with intense public protection strategies tailored to preceived risk. Males are at greater risk of severe COVID-19 complications. Genomic studies are in process to identify differences in host susceptibility to SARS-CoV-2 infection. METHODS Genomic structures were examined for the ACE2 gene that encodes angiotensin-converting enzyme 2, the obligate receptor for SARS-CoV-2. Variants in 213,158 exomes/genomes were integrated with ACE2 protein functional domains, and pathogenicity criteria from the American Society of Human Genetics and Genomics/Association for Molecular Pathology. RESULTS 483 variants were identified in the 19 exons of ACE2 on the X chromosome. All variants were rare, including nine loss-of-function (potentially SARS-CoV-2 protective) alleles present only in female heterozygotes. Unopposed variant alleles were more common in males (262/3596 [7.3%] nucleotides) than females (9/3596 [0.25%] nucleotides, p<0.0001). 37 missense variants substituted amino acids in SARS-CoV-2 interacting regions or critical domains for transmembrane ACE2 expression. Four upstream open reading frames with 31 associated variants were identified. Excepting loss-of-function alleles, variants would not meet minimum criteria for classification as Likely Pathogenic/beneficial if differential frequencies emerged in patients with COVID-19. CONCLUSIONS Males are more exposed to consequences from a single variant ACE2 allele. Common risk/beneficial alleles are unlikely in regions subject to evolutionary constraint. ACE2 upstream open reading frames may have implications for aminoglycoside use in SARS-CoV-2-infected patients. For this SARS-CoV-2-interacting protein with pre-identified functional domains, pre-emptive functional and computational studies are encouraged to accelerate interpretations of genomic variation for personalised and public health use.