In fact, trying to account for that is why colemak uses the zxcv keys where they are, if I'm not mistaken.
So I don't really agree with the notion that you get a huge benefit at all. You are potentially getting some ergonomic benefit in certain contexts (like typing out essays) while at the same time sacrificing ergonomics of keyboard shortcuts you may or may not be able to change and the mental overhead required to remap your muscle memory to fit it.
These tradeoffs are remarkably apparent to me as someone that uses a Kinesis board (and have used a variety of small, bespoke keyboards). There's a lot of tasks that simply aren't suitable for this keyboard, even if I remap the keys with QMK to try to better suit that context. If you need a key to be immediately accessible, having it placed inside a layer just isn't good enough.
With that being said, I'd encourage people to try these things out and see for themselves. I personally don't think they're all that useful, but there's dozens of others that I'm sure swear that using dvorak or workman or colemak or whatever alternative layout changed their life. Just don't expect miracles.
How beneficial it will be depends on your use-case. I personally use Vim with an alternative layout for instance and have zero problems.
The standard ctrl-c/v/x/z is a consideration but it's perfectly fine to have then on another layer or under a combo.
I really do get a huge benefit, as +90% of my time I type inside Vim with the keyboard. Slightly less efficient shortcuts for rarely used programs just doesn't bother me.
For reference I use a 34 key keyboard using qmk.
I have not seen many anecdotes where people get used to an alternative layout, and then revert to using QWERTY because they find QWERTY more comfortable to use.
(Disclaimer: I use Colemak-DH.)
This concern might have been real back on OS/2 and MS-DOS. Not now.
I'm past my 40s- I rather teach my kid to use Dvorak.
I first learned Colemak-DH and I am currently trying RSTHD and I am upto 32 WPM in a few days.
In my 40ies.