I'm sure that using these GUIs would be much easier, but what is the benefit aside from easier setup of using these?
As you indicate, it's easier to setup/configure the GUI vs. command line MAME + a front end.
Most guys that build a cab want the user interface to maintain the illusion by looking and behaving like a real arcade cab which the GUI builds don't do very well since they look and behave like a Windows program.
If there's no cab, there's no illusion to maintain.

You seem to allude to a portable not being ideal to handle a "standard" sort of Front End software (it seems most every build I've seen on here is probably using some Front End).
A control panel (fixed or portable) is just a fancy keyboard/mouse/gamepad.
The main difference between fixed and portable is in the degree of customization and front end integration you can apply.
With a portable panel you are more likely to use default settings so you can more easily connect to different friends' systems.
With fixed panel setups you can customize them more since you aren't playing mix and match.
I haven't gotten much down on paper yet in terms of design, but in my head, I would be able to finagle some way to have standard peripherals (keyboard/mouse), either plugged in, or included in the Panel somehow (obviously not a visible keyboard, that would be gross). Would that change your opinion on using a GUI based MAME?
Doesn't change my opinion, but my opinion isn't the important one here.
If you don't like the look of any of the GUI builds, you can choose any FE you want.
If you design a panel that includes a trackball, joystick, 6-7 buttons, and the admin panel above, you can do tons of stuff like launching programs, browsing the web, switching windows with P1B2 (Alt) + Menu (Tab), switching browser tabs with P1B1 (Ctrl) + Menu (Tab), etc.
You might want to include an unpowered hub and some Neutrik USB feedthrus -- one to connect the hub to a removable external USB cable (see the link in my sig) and one or two that you can use for gamepads for additional players.
Following that point, in terms of design, where should I be looking to do that? I don't think I have any version of CAD or something similar available to me. Are those sorts of programs required or superfluous?
No need for any fancy CAD software.
Sketchup is available for free if you want to do 3-D design.
Check out Gozer's sketchup cab collection
here and there are other people who have models in the warehouse for just about every type of arcade control you might want to add to your panel.
Most of my designs are even simpler than that -- 1:1 PowerPoint like the admin diagram above.

Scott