Game Predictions | Buffalo Bills vs. San Francisco 49ers

49ers storyline to watch: The 49ers haven’t lost three games in a row all season, but they enter this one in peril of doing just that and essentially putting any postseason hopes to rest. The Bills can clinch the AFC East with a win, and they’ve won all five home games this season while scoring 30-plus points in each contest. San Francisco is still banged up and will be traveling across the country after another lengthy flight to Green Bay last week, making this perhaps its most difficult challenge. — Nick Wagoner

Bills storyline to watch: Bills quarterback Josh Allen — a Firebaugh, California, native — will play the team he grew up cheering for. He will have a chance to continue to improve his candidacy for MVP in prime time against a 49ers defense that has forced only one turnover in the past three games and is tied for 20th in points allowed per game (23.6). — Alaina Getzenberg

Stat to know: The 49ers had 18 penalties in their past two games (both losses), which is tied for their most penalties in a two-game span over the past five seasons.

Bold prediction: The Bills will hold running back Christian McCaffrey to fewer than four receptions. No team allows a lower percentage of targets (25%) to opposing running backs than the Bills. — Walder

Fantasy X factor: Bills running back James Cook. Buffalo should rely heavily on its offensive line and running game due to potentially snowy weather, which bodes well for Cook. He scored 15 or more fantasy points in three of their past four games and had 15 or more touches in three of those matchups. See Week 13 rankings. — Moody

Betting nugget: This is the second straight game the 49ers have been underdogs after being favored in 36 straight regular-season games.

Kahler’s pick: Bills 34, 49ers 21

Moody’s pick: Bills 30, 49ers 23

Walder’s pick: Bills 27, 49ers 26

FPI prediction: BUF, 61.3% (by an average of 4.1 points)