If it was com.something you have to type the com first. If "something" is first, you by the time you get to "som" it will probably have something.com in the dropdown list.

I would say its easiest if the most variable part is first, not only for autofill but for the way I think about it.

When you talk about "most significant" you mean the "largest" category. To me the actual most significant is the part that identifies the most unique thing you are typing in, and that tends to be the domain.