How to describe two numbers are different and has difference of 2?

Were you to word it that way, you'd say:

"Two and four have a difference of two."

While it's true that amounts and equations take a singular verb conjugation afterwards, this isn't that because "and" in mathematics (e.g.,story problems) always indicates addition. As such, you could say:

"Two and four is six."

In the above, "two and four" is a phrase that means "2 + 4," and since the sum of two and four, the amount of that expression as a whole, is six, you can use the singular verb conjugation "is." What you've put isn't that, though. In your statement, "two" and "four" are two separate subjects, so being two subjects, they require the plural verb conjugation "have."