The Point of Divergence for this timeline is in the year 1775, when a dysentary epidemic was sweeping through Orange County, Virginia, due to contaminated water. In our timeline, James Madison, who lived in that area was spared, but two of his siblings died from the infected water, probably due to their young age. In this timeline however, the epidemic is stronger, and Madison himself succumbs to the disease.
This POD leads to Madison not presiding over the Constitutional Convention, and therefore, the Virginia Plan is without Madison's strong support for it. In the end, the Constitution is drafted to favor the smaller states, with many larger states such as Virginia and New York outraged. Also, the debate on counting slaves as part of the population of states transforms into a debate on the morality of slavery. Many southern delegates walk out, and in the end, a more progressive constitution favoring the northern states is ratified. South Carolina and Georgia leave the Union due to harsh restrictions on slavery, while the other Southern states remain in, reluctantly.
In the year 1812, several issues with Britain turn to war, and Britain, who is not fighting France at the moment, unleashes her wrath on the fledgeling US. The extreme Federalists' arguments at the Hartford Convention look a lot more appealing, and the New England states secede at the Treaty of Ghent. Britain takes Maine, and New England takes much of upstate New York and Vermont, much to many New Yorkers' dismay. The stage is set for Many Nations, Under God.