While it true that you cannot control which group of ones will form up into a 2x2, you can give them maximum chance by placing 2x2 groups and seeing what happens before adding more for-sale signs. In some cases, I leave some spots as a blank. In most of my starting blocks, I do not mind empty spaces because it makes it easier to fill the food pipeline. If the houses will be developed into large insulae, I can wait that long before adding those last for-sale signs. If it turns out that I will not need the extra population, I might end up putting in good buildings like a theater or a library in those spaces. Another thing that I avoid is designs that intentionally force ones. In the long run, I would rather eventually use the extra water service workers than force ones.
I always estimate consumption of goods in my plan and estimate the number of houses at about one half of the number of for-sale signs. If I will be developing large insulae or better, then I can get something close to the optimum of one quarter.
For small casa houses, I don't try very hard to form 2x2s since there is no goods consumption. I do make some effort because it will effect my prosperity cap. Reducing the number of small casas that go into the formula will mean that my other housing has a larger relative importance.