World triathlon champion Jonny Brownlee will miss the San Diego race on 20 April because of an ankle injury.
Brownlee, who claimed a bronze medal at the 2012 Games, triumphed in the race last year en route to winning the ITU world title.
"Not being on the San Diego start line will be very tough," he told BBC Sport.
"I haven't started training properly so I don't know when I'm going to start racing. Hopefully, it'll be at Yokohama unless something else goes wrong."
His brother Alistair, the Olympic champion, will still compete in America but Jonny will have to sit it out as he continues to recover from injury problems which were sustained in a race in Yorkshire.
"It's been a combination of a few injuries but the first major one was when I tore a tendon in my ankle," he explained.
"I raced the Yorkshire cross country championships and it was on a really rough course.
"I turned up and there were a load of little kids who had stayed to watch me run and thought I can't not do it. To this day I wish I hadn't run that race."
Participants have to race in four of the seven rounds of the World Triathlon Series to qualify for the Grand Final in London in September.
Brownlee added: "I can afford to miss San Diego and give myself more time. I am considering going to Yokohama next month to get my season under way there. I've not raced the World Series there before so that will be something to look forward to, and of course my focus is on getting to the Grand Final in London in the best shape that I can."