Whole-exome-sequencing (WES) of patients of Italian ethnicity (n = 6939) found many missence variants, notably, three common ones with highly destabilizing, protein-structure interference predictions (Benetti et. al). These variants are not present in East-Asian populations. Rare variants were also identified.
- p.(Asn720Asp) (n = 103)
- p.(Lys26Arg) (n = 11)
- p.(Gly211Arg) (n = 12)


The image below shows case-control variant distribution. While no variant was significantly enriched in the population, control cases had a significantly higher ACE2 allelic variability compared to that of patients. No causal relationship between ACE2-variation and COVID-19 severity can be made to date.

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Allelic variants in the ACE2 gene has been observed in different ethinic populations, as well as in case-control studies within ethnic groups. However, these are present in relatively low frequencies. Functional studies are encouraged to characterize the relationship between ACE2 variants and COVID-19 severity, but no causal relationship can be made to date.

ACE2 variants and COVID-19

Benetti, E., Tita, R., Spiga, O. et al. ACE2 gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population. Eur J Hum Genet (2020). doi: 10.1038/s41431-020-0691-z https://www.nature.com/articles/s41431-020-0691-z#citeas

ACE2 gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population

ACE2 Variance in the Italian Population

This graphic shows the distribution of 61 potentially harmful ACE2 polymorphisms by population using variant assembly of databases, annotation of non-synonymous polymorphisms, and predictive-deleterious scoring. 
- databases: Genome Aggregation Database, Exome Sequencing Project, and 1000 Genomes Project (1KGP, www.internationalgenome.org)
- non-synonymous variant annotation: ANNOVAR
- deleterious assessment: CADD and Polyphen2 

The top bar shows ACE2 functional domains, and the vertical notches represents population counts of the respective variant. The heat map depicts polymorphism frequencies found within the different populations.

- 39% of variations occur in African/African-American (AFR) populations
- 54% of variations occur in non-Finnish European (EUR) populations
- Amish (AMI) and Ashkenazi Jewish (ASJ) populations do not appear to have any of these polymorphisms
- variants such as p.Arg514Gly may influence COVID-19 pathogenesis and its associated cardiovascular conditions by altering the AGT-ACE2 pathway

Population group legend: AFR, African/African-American; AMI, Amish; AMR, Latino/Admixed American; ASJ, Ashkenazi Jewish; EAS, East Asian; FIN, Finnish; EUR, Non-Finnish European; SAS, South Asian; PNA, population not assigned

Nonsynonymous ACE2 Variations by Population

ACE2 is cleaved by TMPRSS2 as a secondary function of the serine protease at at Arginine 697 to 716 to further facilitate viral entry. This suggests that populations such as non-Finnish Europeans that carry ACE2 polymorphisms including p.Arg708Trp, p.Arg710Cys, p.Arg710His, and p.Arg716Cys may have milder COVID-19 symptoms.  These mutations cause ACE2 to lose their cleavage sites, so TMPRSS2 cannot cleave the enzyme in the same way and causes the receptor to change its conformation.  

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