Put it near the end of a reaction beat, after the setup has landed, then follow it with Anime Ahh for a double-take or Yamete Kudasai when the scene keeps escalating.
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This is a very short anime groan lasting under a second, a single strained vocal sound with no words. It lands as tired, exasperated and a little awkward, the kind of noise a character makes when something goes wrong or drags on too long. Its clipped length makes the reaction feel sudden and blunt, so it works best as a quick comic beat rather than a drawn-out moment.