Owen Farrell suffered an injury while training with his club Saracens this week, ruling him out of his return to club action this weekend after missing the last two months with an ankle problem.
He was set to make his return to club action against London Irish in the Challenge Cup this weekend after suffering the injury against Australia in November.
England are set to join up at a training camp in Brighton on Monday ahead of their Six Nations opener against Scotland at Murrayfield on February 5.
Farrell won't be at the camp with George Ford, who started the World Cup Final in 2019, favourite to replace him having missed out on Eddie Jones' original squad.
Marcus Smith looked likely to start in the number 10 jersey with Farrell at centre and England fans will be excited to see more of the young Harlequins star.
It is now looking likely that Nothampton's Courtney Lawes will take on captaincy duties for at least the Scotland game with it being unclear whether the 30-year-old can play a role in any of England's games.
"Owen Farrell suffered an injury in training this week ahead of the game against London Irish, ruling him out of the match," said Saracens in a statement.
"Owen was back in full training having recovered from the ankle injury he sustained against Australia during the Autumn internationals.
"We will have a further update after he sees a specialist early next week."
