I have used ergo keyboards with thumb clusters for several years now. After a while, even though switching to a split ergo keyboard alleviated wrist pains, I developed thumb discomfort.
In the end I solved it by only frequently using the resting key of each thumb (space and backspace). And using the other thumb keys for infrequent things. I use homerow mods to have all modifiers in the alpha block.
if you find one you like it's a massive difference in how much usage you can get out of your thumbs while typing
Until they start to hurt. It can take a few years (just like wrist pains). Be careful!
I have homerow mods configured but still need to work on using them more. Unfortunately a lot of what's best for typing conflicts with what's best for gaming. Almost every example split layout puts space on the right half and I move it to the left. Still need shift and control on pinky holds. And the Elora has an exaggerated pinky stagger but swapped to WQSD makes an almost perfect diamond, but at the expense of the old Q now being A is below instead of above and Z is really far away.
Mirrored home row mods are even much nicer (IMO).
Also, RSI on your thumb (especially with smartphone usage) is very common.
So yes, you should probably have the most frequent keys on your thumbs but only very few (I'd say 1-2).