You know what's so devastating to me about "God that I were a man"? It's the way that in this situation, Beatrice is not exceptional. In the first acts, she appears to be exempt from the gender roles that everyone around her complies with: she has avoided marriage so far, and she has license to playfully criticize and reject being "over-master'd with a piece of valiant dust" (2.2.55-56). She even suggests to Hero that she claim some agency over her engagement: "it is my cousin's duty to make curtsy, and say, 'father, as it please you.' But yet for all that, cousin, let him be a handsome fellow, or else make another curtsy and say, 'father, as it please me'" (2.1.48-51). Beatrice has carved out an existence for herself that everyone else tolerates; her wit allows her to live outside of people's expectations of womanhood.
But Beatrice is not exempt from being a woman. When it actually matters, when Hero is disgraced by powerful men with no regard for her wellbeing or humanity, Beatrice can't do anything about it. And "God that I were a man" is so painful because it reminds us--and Benedick--that no matter how transcendent Beatrice appears to be, she is still constrained by her role in Messina's society. Back in act one and act two, the reason that she was allowed to poke fun at men wasn't that she couldn't be stopped; it was that it didn't matter. She has no actual power to change the order of things, and so her verbal sparring is not a threat.
(An aside: I think that Benedick is taken aback by "God that I were a man" because this has never really occurred to him. He sees Beatrice as his intellectual equal, and he has watched her carve out space for herself effectively (they know each other of old). In the 2011 production with David Tennant, the costuming and acting choices show how Benedick starts actively performing masculinity only when he accepts Beatrice's request to kill Claudio--when he has to "be a man for [Beatrice's] sake" (4.1.314). In the first acts, he wears tight clothes, a crop top, and a miniskirt. From the wedding on, he wears his military uniform and then a suit. His body language also changes; he abandons physical comedy, stands tall, and emotes less when he speaks to Claudio and Don Pedro. He wields his masculinity as a weapon because he now realizes it's a weapon that Beatrice cannot wield herself.)
The crashing realization of Beatrice's limits is so devastating to me because it's so familiar. I can only speak from experiences I've had, but as a queer woman I know that tolerance is different than empowerment. That having grown up evading dating and romance with made-up excuses to hide my queerness, having realized the extent of the misogyny in an organization I cared about and having grappled with how that misogyny prevented me from effecting change, being allowed to exist is not the same as being able to participate, to make things different. God, that I were a man. I would eat his heart in the marketplace.