Robbie Henshaw has failed to recover from hamstring trouble in time to make his World Cup debut against Romania on Sunday.
The Connacht centre is likely to be the only member of Ireland's squad left awaiting World Cup action after this weekend if boss Joe Schmidt empties his entire bench at Wembley Stadium.
Ireland had hoped Henshaw would be available for selection but, while close to recovery, he has not taken full part in training at any stage this week.
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Head coach Schmidt has made 12 changes to the side that saw off Canada 50-7 in Cardiff last weekend for Ireland's second clash in Pool D.
Ulster centre Darren Cave slots in at 12, where Luke Fitzgerald had deputised for Henshaw at the Millennium Stadium.
Ian Madigan starts at fly-half, leaving Ulster's Paddy Jackson primed for action from the bench.
Only Jared Payne, Keith Earls and match-day captain Jamie Heaslip are retained from the starting line-up against Canada.
Cian Healy, makes his first Test start since neck surgery in May, having returned off the bench against the Canucks in Cardiff.
Tommy Bowe, has a chance to shake off his dismal showing in Ireland's 21-13 World Cup warm-up defeat against England at Twickenham on September 5.
The Ulster flyer was bumped off by Jonny May for England's opening score that day and endured a frustratingly below-par afternoon.
Dave Kearney, has sneaked ahead of him in Ireland's pecking order, so the powerful Ulster man will be desperate to impress against Romania.
Ireland will be fully expected to ease past Romania in much the same vein as against Canada, hence the raft of changes from Schmidt.
The pivotal clashes in Pool D remain further ahead, with Italy and France the two main challengers for the top spot in the group and a likely quarter-final against Argentina.
Simon Zebo's selection at full-back to cover for Rob Kearney indicates how far the Munster flyer has slipped down the wing stakes.
How important will Henshaw's absence be for Ireland?
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