There could be up to 40 players from the top flight jetting off to west-central Africa to contest the 24-team tournament, which is the continent's football showpiece.
Premier League clubs have to decide when to release the players to the tournament that was previously delayed because of the global pandemic.
It is due to kick off on January 9 in Yaounde with the final on February 6.
The European Club Association, an independent body which represents clubs across Europe, has expressed concern due the recent discovery of the new Omicron variant of Covid-19.
It has been suggested the dates and location could change - possibly to Qatar - but this has been dismissed by The Confederation of African Football.
Scroll down and click through to see which players could be absent and which club is most affected.
5. Burnley
Likely: Maxwel Cornet (Ivory Coast) Games impacted: Jan 2: Leeds (A); Jan 15: Leicester (H); Jan 22: Arsenal (A); Feb 8: Man Utd (H)
6. Chelsea
Likely: Edouard Mendy (Senegal), Hakim Ziyech (Morocco) Games impacted: Jan 2: Liverpool (H); Jan 15: Man City (A); Jan 23: Tottenham (H); Feb 8: Brighton (A)
7. Crystal Palace
Likely: Cheikhou Kouyate (Senegal), Jordan Ayew (Ghana), Jeffrey Schlupp (Ghana), Wilfried Zaha (Ivory Coast) PL games impacted: Jan 1: West Ham (H); Jan 14: Brighton (A); Jan 23: Liverpool (H); Feb 8: Norwich (A)
8. Everton
Likely: Alex Iwobi (Nigeria) PL games impacted: Jan 2: Brighton (H); Jan 15: Norwich (A); Jan 22: Aston Villa (H); Feb 9: Newcastle (A)