On a twisting turning circuit around Birmingham, which included a series of punishing climbs, six-time Paralympic champion David Weir looked to be coasting to victory.
But an untimely puncture allowed England's Johnboy Smith to catch him with just six miles remaining, upgrading the silver medal he won four years ago on the Gold Coast.
Frame, 25, also overhauled Weir, who won gold at Glasgow 2014, before holding off England's Simon Lawson to win silver by just ten seconds.
"This means the world to me, all those years of training, the countless miles, going out in every sort of weather, it takes so much out of you physically and mentally, but it's paid off," he said, after clocking a 1:45:49 season's best.
"I couldn't have done anymore, I'm just exhausted, I gave absolutely everything I could have done.
"It was such a demanding course; the gradients were pretty insane, and I've never really experienced that before. I just tried to stick with Simon, and I knew I could kick away from him.
"When Simon passed me, I thought I’m not letting this happen and just pushed for my life.
"I’m buzzing, I can’t believe it’s my first senior team, first Commonwealth Games and I’ve won silver."
Newton Wamphray’s Frame is coached by Joyce Rammell at Red Star AC and hopes to use this performance to springboard on, with the Paralympics in Paris just over two years away.
"This is the biggest competition of my career, the calibre of athletes here is amazing and just to be part of it shows what potential I have," he added.
"Coming into the last stages I could hear my mum shouting me on even within all the other shouts. My dad helps train me and he is just ecstatic. It’s a happy family."
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