The Eclipse Phase APs on RPPR are some of my favorites, and the setting is the first since Planescape that really interests me. I was introduced to the concepts of posthumans and transhumanism by Dan Simmons' Illium/Olympos cycle (which I do not recommend, btw) a decade ago but have largely been disappointed by the slow adoption of the genre, especially by videogames.
Last week, though, I came across a little game on Steam called Sundogs (actually it was recommended by whoever runs the Fail Better Games Facebook account, they're the guys that made the awesome Sunless Sea and are behind Fallen London, both of which I heartily recommend looking into) and I think it marks the first actual, no holds barred posthuman vidya game I have ever played. Unfortunately, it is also a rather barebones, experimental 95% text only 'interactive experience.' In other words, it's barely a game, and what game is there is mostly comprised of reading, random luck and choosing to go certain places after certain textual triggers.
Regardless, what is there is interesting and compelling (though I hesitate to call it 'fun' or 'good',. or necessarily worth the 10$ price tag), all the classic hallmarks of posthuman transhumanist scifi: cortical stacks, sleeving and upload facilities, Dyson cylinders and other various habitats, integrated data systems, fabricators, etc etc. The prose is simple but suggestive, though it is probably a little light on description and explanation for those unfamiliar with the general tropes. Personally I was disappointed by the lack of interpersonal interactions (and the far too random aspect of exploration 'gameplay,' but whatever).
I have a pretty wide ranging knowledge of videogames but I'm pretty sure this is the first I'd specifically call classically 'posthuman.' The Deus Ex games could almost be considered 'early era' transhumanist but that would really really be stretching the definition, they are much more 'cyberpunk,' which is really where most vidya scifi seems stuck: the same can be said of System Shock 1 and 2, Shadowrun Returns, etc. Some argue that Bioshock, Metal Gear and Halo have transhumanist elements as well but they do not take place in posthuman settings.
Perhaps the closest thing I have encountered (outside of Sundogs) is a weird little French FPS called EYE: Divine Cybermancy but honestly this might just be because the game story and background setting is nearly impenetrable due to what I can only assume is a rough translation. EYE is so weird I can't even really talk about it, and I'll admit to never getting more than 2 or 3 hours into it as a result.
I was hoping that maybe some other fans of the genre were aware of more obscure titles, or ones I forgot to mention?