Garry Ringrose is out of Ireland's Six Nations clash with Italy tomorrow.
Ringrose, 28, has been battling with a calf injury since last week and, although named in the side yesterday, woke up feeling tight and was pulled from the side.
He joins senior stars Johnny Sexton, Peter O'Mahony, Tadhg Furlong and Tadhg Beirne on the absentee list.
It means that Ireland will have seven changes to the line up that started the victory over France almost a fortnight ago.
The loss of the Leinster centre is a blow to the player himself as he was due to win his 50th cap, but also to head coach Andy Farrell as Ringrose's experience would have helped half backs Ross Byrne and Craig Casey, who are starting a Six Nations game for the first time - and also playing together from the start for the first time.
Stuart McCloskey, who was dropped to the bench to accommodate Bundee Aki coming back into the side after strong displays off the bench in the opening two games of the tournament, is back in the line-up in place of Ringrose.
Jimmy O'Brien, who started the three November internationals but hadn't featured in the championship to date, is added to the bench.
"Garry picked a bit of knock up on his calf last week," explained Ireland's backs coach Mike Catt after the squad's Captain's Run at the Stadio Olimpico this afternoon.
"We've sort managed it through the week and unfortunately, I think due to the travel and everything yesterday, he's woken up a little bit tight.
"He's obviously very, very disappointed because it was going to be his 50th cap, so he's out.
"But it does give Stuart McCloskey, who is coming back into the team, and Jimmy O'Brien an opportunity to play in a side that's flying at the moment and gives them an opportunity to show what they're about as well."
Asked if Ringrose's injury was a long-term problem, Catt denied that was the case. However, it does make him a doubt for the potentially vital clash away to Scotland in just over two weeks' time.
"He hasn't pulled anything or done anything like that. It's obviously very disappointing for him," said Catt, who insisted that the dynamic of the team won't change despite almost half of the side that started last time out being sidelined for this game.
"No...as a group, that's where we're still learning.
"Bundee and Stuart have both got an understanding of how we want to play - obviously they will play to their strengths, make no bones about it.
"But they're quite capable of playing any game that we decide to play, whatever the defence gives us they will make the right decisions on the back of it so it's exciting times.
"And obviously defensively it's two big guys there that can show a real physical dominance there in the centres, so it's exciting times for those two.
"We've obviously got a load of injuries that are out, some of the top guys in world rugby are out at the moment and I think the guys have fitted in seamlessly, with James Ryan coming in as captain again.
"I think you've also got to look not necessarily just at James but Iain Henderson, Ross Byrne, who is a calming voice, Hugo Keenan - all these guys have been around for quite a while.
"There is a good leadership group there and it gives them something to focus on.
"But I think they've been exceptional throughout the week, they've really driven the team the way we want the team to go, so let's hope the performance can do that."
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