Clark's wife, Kelly, posted the news on her husband's Twitter account.
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"I'm heartbroken to tell you that today I lost my best friend and husband," she wrote. "He passed peacefully surrounded by many of the people he loved most. I am thankful for all of Dwight's friends, teammates and 49ers fans who have sent their love during his battle with ALS."
Clark was on the receiving end of "The Catch," one of the most famous plays in NFL history. In 1982 it helped the 49ers get to the team's first Super Bowl. Clark went on to become a pro bowler -- and now has his 49ers jersey retired.
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Clark, who suspected his years playing football lead to the condition, announced his ALS diagnosis in March 2017. In an open letter, Clark said started experiencing the symptoms of ALS in his left hand back in 2015.
49ers CEO Jed York released a statement after Clark announced his diagnosis, saying he was "deeply saddened" and that he would receive full, unconditional support from the team and staff.
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"Many know Dwight as an iconic figure in 49ers lore, whose accomplishments on the field brought joy to fans around the world. Our organization is fortunate to know him more intimately as a wonderful man who has given so much of himself as an ambassador to the entire Bay Area. We will stand alongside Dwight and his family as they wage this battle," York said.