If you count disabilities that don't exist in the real world, SaGa Frontier 2 would qualify.

One of the main characters, in fact probably the one character most important to the game's plot, is Gustave. Gustave is unable to use magic at all. In fact, he lacks Anima (which is supposed to be found in all forms of life). In fact, this disability is so looked down upon that he is kicked out of the royal family as a result. One very important part of the plot is how he manage to persist despite this disability, and how he creates weapons made of steel, eventually coming to rule much of the world.

From a gameplay perspective, Gustave doesn't get that much gameplay time, but when you get to control him, he is the only playable character who is unable to use magic. This reminds me of one possible game idea I have, and I am wondering if it's been done.

The game would be an interactive fiction game (that is, a text based adventure) in which the main character is blind. There would be no graphics, and all the descriptions would lack any visual information. The text might describe things like what you hear, what you smell, and, of course, how things feel when you touch them, but there would be no information about what you see (because you can't see). Similarly, the "look" command would be unavailable, but you would get other commands like "listen" and "feel" that let you know what's going on.

You mean Dark Echo, don't you? If so, it's also available on PC.

The, there are also other games with similar premises like Beyond Eyes or Pulse (which is probably the one Shadowstalker16 is referring to?)

The wheelchair brings up an interesting point.

In X-Men Legends, Dr X starts as an NPC, in his wheelchair, he talks to you, gives you missions, but as soon as you unlock him, his wheelchair is gone and he is running all over the place. :P

Some people would say that A) Isn't true to the comic and B) it's a disservice to people in wheelchairs insinuating he would have been totally useless had the game not all of a sudden let him be able to walk.

Like disability to spell English words correctly?
I wish Professor X was playable character in Marvel games.

That sound pretty much like Grail to the Thief. It's a text adventure that can also be played without any visuals, only audio.

Wow that's very very interesting. Bookmarked! I always wondered when games would try immersion via non-visual ques (no, don't bring the kinect into this).

It's not the entire game, but you play the last part of The Walking Dead having only one hand. Not sure if it counts.

Also HuniePop.

*badum tssh*

I'm not familiar with that game.

*cough*

Deus Ex: Human Revolution. The protagonist is crippled early in the game and fitted with extensive prosthetics... :p

I always thought Commander Keen was developmentally disabled (because of the helmet and how he "sees the world"), but apparently he's a genius? News to me!!! 20 years later!

Also comes to mind: Joker from Mass Effect, who has brittle bone disease (and is amazingly well voiced by Seth Green - even looks like him).

Wellll..... to cower point A) you could argue it is the cloned body he got after his original body was destroyed when it was used to hatch the Brood queen... perfectly canon.

Which goes to further prove that I need to stop talking out of my ass. :P

Does God Hand count?