Robbie Henshaw has been ruled out of Connacht's European Challenge Cup game against La Rochelle on Saturday by an ankle injury which may also be a concern for Ireland coach Joe Schmidt.
Connacht said on Tuesday that Henshaw, 23, sustained a "low-grade ankle sprain" against Exeter on Sunday.
Henshaw started in Ireland's autumn wins over South Africa and Australia.
Jared Payne, Henshaw's centre partner against the Springboks, returned to the game last weekend after two months out.
Payne was selected at full-back for Ulster in the European Champions Cup hammering by Toulon in his first action since picking up an ankle injury in the Test against South Africa in November.
With Ulster's Stuart Olding out for at least 10 weeks because of an elbow injury, Leinster duo Gordon D'Arcy and Luke Fitzgerald appear to be Schmidt's other principal centre options for the Six Nations opener against Italy on 7 February.
Another Ulster player Darren Cave could also be in contention for a Six Nations squad place.
Schmidt's squad is likely to be boosted by the availability of Leinster and Lions duo Cian Healy and Sean O'Brien.
Prop Healy has been out since sustaining a serious hamstring tear in September while flanker O'Brien is close to a return after suffering a recurrence of a shoulder injury in the early weeks of this season.
Neither forward will feature in Leinster's crucial European Champions Cup game against Wasps on Saturday.
The injured duo were not registered for the pool stages of the competition although one of them could have been drafted into Matt O'Connor's squad for the game in Coventry.
Meanwhile, Connacht have further fitness worries in addition to Henshaw for the game against La Rochelle.
Centre Dave McSharry sustained concussion in Sunday's Challenge Cup defeat by Exeter and will continue to be monitored this week.
Fly-half Craig Ronaldson has been ruled out for two to three weeks because of a quad muscle problem after being forced to withdraw from the game against Exeter.
On the plus side, Tiernan O'Halloran, Jake Heenan and Ireland squad contender Nathan White could all feature this weekend after returning to fitness.
New Zealand-born prop White was in line to make his Ireland debut in the autumn games before suffering an arm injury in a national squad training session.