I have all my mods on thumb keys (all 1x size in a cluster of 4 on each) and can access all possible combinations with small shifts of my thumbs. On my left I have Shift, Fn, Backspace, Tab. On my right I have Ctrl, Alt, Space, Enter. The ones used in combinations (Shift, Fn, Ctrl, Alt) are on the upper keys so I use a squeeze movement to press and hold them. The "struck" keys (Tab, Backspace, Space, Enter) are on the bottom so I can use a downward strike to press them.
Del is top right on my right hand, so I squeeze Ctrl and Alt with my right thumb and press Del with my pinkie. Easy-peasy and somewhat similar to using the right hand Ctrl and Alt on a WinkeyLess. Esc is the other "modifier" which is on the top left of my left hand.
This works perfectly for me and I don't find any combinations difficult, even some of those weird ones in Excel, so my advice is to find a mapping that really works for you and offload the mods from the pinkies as much as possible. Then take the time to train your muscle memory.