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It’s because nouns in Spanish carry gender! Which is crazy but it works.
“San Francisco” → Francisco is a male name.
“Santa Bárbara” → Baŕbara is a female name.
Masculine form would be santo like in Santo Domingo. San seems to be an abbreviated form of that.
SANTO FRANCISCO, THE EVEN GAYER SAN FRANCISCO 🏳️🌈🏳️⚧️🏳️🌈🏳️⚧️❤️