SANTA CLARA, Calif. — The San Francisco 49ers are likely to be without three of their best offensive players and could be missing two of their best defenders on Sunday against the Los Angeles Rams.

After missing practice on Thursday and Friday, tight end George Kittle (hamstring) is officially listed as doubtful for Sunday. If Kittle does not play against the Rams, he would join running back Christian McCaffrey (calf/Achilles tendinitis) and receiver Deebo Samuel (calf) as key offensive options ruled out.

On the other side of the ball, defensive end Nick Bosa and cornerback Charvarius Ward, two of the Niners’ top defenders, are listed as questionable. Coach Kyle Shanahan said Bosa suffered a rib injury during a one-on-one period Thursday and was limited in that practice and again on Friday.

Ward also missed Thursday’s practice with hamstring and knee soreness, but he participated in Friday’s practice on a limited basis. Kittle and Ward were surprise additions to the injury report on Thursday after practicing in full on Wednesday.

“[Kittle] and Charvarius, they were sore after practice [Wednesday], like a number of guys are,” Shanahan said. “They came in Thursday morning and were still sore. And still today with Kittle. That’s the severity of it.”

In better injury news for the Niners, safety Talanoa Hufanga has been cleared to return after recovering from a torn ACL in his right knee. Hufanga was listed as doubtful in the first two weeks as he worked his way back into the mix but has no designation against the Rams and is good to go.

Shanahan said Hufanga is prepared for the game, and how much he plays will be based on how things go series by series. That means George Odum and/or Malik Mustapha could get some work opposite Ji’Ayir Brown at safety.

Still, Hufanga is excited to be back after a long rehabilitation that he has done his best to view as a positive both personally and professionally.

“For me, it was opportunity to be around my family,” Hufanga said. “It was an opportunity to dive into the playbook, dive into the film room. And so, I never really looked at it as a bad process to go through. Everybody’s been through something and I think this was just my story and my process. And so, when I looked at it, there’s so many positives from it versus negatives and I think a lot of people can get caught in the negatives and it will affect your healing for sure … I’m just really happy to be back.”

Kittle, meanwhile, made it through last week’s game against the Minnesota Vikings despite needing an IV at one point. If he can’t play against the Rams, the Niners would likely turn to veteran Eric Saubert to start in his place.

“I thought he’s done a hell of a job,” Shanahan said. “He’s stepped in well. Kittle was cramping most of the game so [Saubert] had to do a lot throughout the Minnesota game and he’s been real consistent since he’s been here. If he’s got to do it all, he’s up for the challenge.”

Jake Tonges is the only other tight end on the active roster, though Brayden Willis and Mason Pline offer practice squad options who could be elevated for depth.

The Niners have rarely played without McCaffrey, Samuel and Kittle since McCaffrey arrived via trade in 2022. Quarterback Brock Purdy has had just 10 plays in 33 games without McCaffrey, Samuel and Kittle on the field. He’s 3-of-7 for 49 yards with no touchdowns and an interception on those plays, though half of them came in mop-up duty against the Chiefs in 2022 before Purdy was the starter.

On Thursday, Purdy was quick to note that even if Kittle can’t play, the Niners still have plenty of options, including receivers Brandon Aiyuk and Jauan Jennings and running back Jordan Mason.

“Obviously it sucks not having your guys,” Purdy said. “It’s like, ‘All right, how can we figure out to get the ball to other guys?’ We’ve got playmakers. I’ve said that before. We’ve got a really good scheme, great playcaller and some great players that step up in the roles and do their job really well. I still have to do my job in terms of my reads and my progressions, more so than I need to now change the way I think and make sure I’m getting it to this guy or that guy because a couple guys are out. It’s not like that.

“That’s the challenge for me, is how can I continue to be better with my progressions and as a quarterback and handling situations, being as efficient as I can regardless of who is in. That’s where my mindset is at with this game. And obviously, I’d love to have my guys back and playing with them, but that’s just how it is with this game sometimes.”