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There's a very useful function in all music sequencer software which is called MIDI draw, or draw edit, or something similar. It also exists in video editing software, for sound volume and panorama fades. Today it occured to me that it could be very useful in TVP, too.
Imagine a layer like this. Only some frames are drawn, there's a repeat setting at both ends. Now a switch would toggle the normal opacity setting to this "draw opacity" setting. The layer will change colour so it's clear it now extends to the whole project. There's a thin line now, default could be the last used global opacity setting. Clicking on the line creates a key which can be moved vertically or horizontally later. Vertical movement prompts that little number box to show, clicking inside makes the value editable.

Horizontal key position should be restricted to center of frame.

As you see in my example, the repeated animation is invisible for some frames, then fades in, stays at full opacity, and fades out again.

Toggle to global opacity should not erase the keys.

I'm a big fan of non-destructive workflows and really like the idea, but everything non-destructive has to potential of slowing down TVPaint I guess?

Not in this case, I think, because the opacity setting is already there. Each frame has to be calculated, it makes no difference if all with the same opacity, or if from a table with different opacity values for each frame.