A new dark wizard who is jealous of Harry and Hermione's power and knowledge. This wizard wants to use their disappearance to create chaos in the wizarding world so that he can rise to power. He has been secretly studying their every move and finally finds a way to make them disappear.
Voldemort could be the antagonist. Even if he was defeated in the original story, there could be a scenario where some remnant of his dark magic causes Harry and Hermione to disappear. Maybe he had a secret plan that was set to activate after his death and it involved taking them out of the picture.
Perhaps a powerful magical being from a different realm is the antagonist. This being might mistake Hermione for someone else or see her as a key to something in the wizarding world. So, it uses its magic to make her disappear. This being would be very difficult to defeat or negotiate with, making it a huge challenge for those trying to find Hermione.
It could be Salem. She has always been interested in the power of the silver eyes, and Ruby having those eyes makes her a prime target. Salem might send her minions to kidnap Ruby, which would lead to her disappearance.
A group of rogue demigods could be the main antagonists. They believe that Percy is too powerful and his presence is causing more problems than solutions in the demigod world. So they make him disappear. But when Percy comes back, he shows them that they were wrong and that they have been mislead by false beliefs.
It could be a new dark wizard who has been secretly plotting in the shadows. This wizard might be jealous of Harry's fame and power, and decides to make him disappear so that he can rise to power unopposed. He could have a group of followers who are experts in dark magic and are able to carry out his plan to make Harry vanish.
Another possibility is an ancient evil that has been awakened. This entity might see Hermione as a threat because of her potential power. So it curses her to stop her from growing stronger. In this case, the antagonist would be very powerful and mysterious, and Hermione and her friends would have to do a lot of research and exploration to find a way to defeat it.
It could be Dumbledore. Even if he's dead in the original story, in fanfiction, anything is possible. He might have left behind some kind of magic that allows him to train Harry from beyond the grave, or he could have faked his death to take Harry to a secret location for training.
Perhaps Harry is kidnapped by a mysterious and powerful magical being. This being has the ability to make Harry disappear without a trace. His friends then embark on a dangerous quest to find him, facing many magical challenges along the way. They might have to search in hidden and dangerous parts of the wizarding world that they have never been to before.
Another possibility is a dark wizard or a group of dark wizards who are after some powerful magic that the Lestrange family has, and Hermione gets in their way as she tries to protect the family or uncover the secrets. They would be the main force that Hermione has to face and overcome throughout the fanfiction.
It could be Draco Malfoy. In some fanfictions, Draco might be pushed to such an extreme by his family's beliefs that he resorts to physical violence against Hermione. He might punch her out of jealousy or to assert his so - called superiority.
The antagonist could be a magical creature that has infiltrated Hogwarts. Maybe it's a mischievous imp that targets Hermione because it senses her strong magical aura. The imp then causes the homework sabotage and tries to make it look like Hermione is responsible. Or it could be an older student who feels threatened by Hermione's academic success and decides to set her up by making it appear she's sabotaging homework.