Any of the Bay Area Bridges would be a disaster.
We had the Bay bridge closed for several weeks after the Loma Prieta earthquake. It wasn't fun, but, since the BART tube came through it OK, life wasn't impossible. We also have CASR-92, I-580, CASR-84, -237, and -37 to get you around or over The Bay. We have I-280, -580, -880, and -980 as alternates for each other. We have quite a bit of built in redundancy such that, once the immediate problem is resolved (people get off of the Bridge that had the initial problem), long term people can work around most closures. For example, CASR-99, I-5, and US-101 (and to a certain extent US-395 and CASR-65 where built can, if you know about a problem far enough in advance, be used in place of each other. Same goes for US-50 and I-80. Same goes for CASR-41, -46, and -58. Also, CASR-25, -152, and -156. Now, I won't say that we have a lot of excess capacity to deal with any single failure, but people would be able to get where they want to go.
My hunch is that there is a bridge over some gully along either I-8, -10, or -15 around which it might not be possible easily to work. Once again, as long as it were only one gully on one of these roads, before long people would figure a way around it (possibly using one of the others mentioned), but, off hand, it looks like there would be serious diversions for those who are unprepared.
If you want to cause the most inconvenience to the most people for the longest period of time, find a heavily populated island group with water that is too shallow to take ocean-going vessels. So, my guess is that you might find such a bridge in the Florida Keys.