Shaquem Griffin, 22, was selected by the Seattle Seahawks in the fifth round of the NFL Draft on Saturday.
His hand was amputated when he was four years old due to a painful condition that meant the fingers of his left hand had not fully developed.
Griffin still went on to become a star linebacker at University of Central Florida, becoming the American Athletic Conference defensive player of the year in 2016.
Friends and family jumped up and down and cheered when TV reports confirmed he had been picked – as the two twins tightly embraced one another.
His brother, Shaquill, was a third-round pick for the Seahawks in 2017.
“I don’t see it as a handicap and I have never looked at it that way,” said Shaquem.
“I hope I am an inspiration for people, to see I can do whatever I want. I haven’t seen anything I couldn’t do. I’m never going to let someone put a label on me.”
Griffin’s athletic ability stunned onlookers at the NFL Combine trials in March.
He bench-pressed 225 pounds (102kg) 20 times with a prosthetic hand and then covered the 40-yard dash in 4.38 seconds.
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The competitiveness and physicality of the NFL has made it difficult for players with a disability to be considered.
But with Griffin now the league’s first one-handed player attitudes could be set to change.