Downside of not rendering a region in twig template?
Drupal won’t care and it won’t have any side effects other than the contents of a region not being rendered to a page whose template doesn’t render it


It's not quite that simple.

The problem with dynamically not rendering a region is that Drupal doesn't know about that. It will still load, check and prepare those blocks on every page, which means it is unecessary overhead compared to defining visibility rules to only have it shown on the frontpage. You can also do an empty check of the region in the template and as a result, only have it printed if there are blocks inside (this doesn't work reliably with blocks that might be shown but might be empty but it should work if they are configured to not be shown).

You could also implement a hook_block_access() implementation and deny view access for all blocks in a certain region, then you don't need to manually configure them all, but it does need to be in a module.