TCN2: The reason you’re tired
Last week, we touched on the CUBN gene and B12. Today, let’s continue looking at the B12 pathway, this time assuming the CUBN gene is functioning properly.
REFRESH:
Once we ingest B12, here’s what happens:
In the stomach, B12 is first freed from food by stomach acid and enzymes.
It initially binds to a protein called haptocorrin (also called R-protein).
Then, in the small intestine, pancreatic enzymes degrade haptocorrin, and B12 binds to intrinsic factor (IF). This is a protein made by the GIF gene.
This B12-IF complex travels to the ileum, where it’s absorbed by cells expressing the CUBN gene, which produces cubilin, the receptor that recognizes B12–IF and lets it through the gates to our bloodstream.
Once inside the bloodstream, B12 binds to transcobalamin II, encoded by the TCN2 gene, which delivers B12 into cells.
Inside cells, B12 is converted into its active forms:
Methylcobalamin (used in methylation)
Adenosylcobalamin (used in mitochondria for energy metabolism)
Okay, now back to where we left off:
Let’s say everything was functioning properly until step 5… Here, you have a less favorable variant of the TCN2 gene. (GG or CG the G allele is the risk one, not C). This means vitamin B12 doesn’t bind well to transcobalamin II (TCII), which is the protein responsible for delivering B12 into your cells. So B12 is floating in your blood, but not entering your cells. That means your cells are starving, especially the ones that depend on methylation to function optimally.
This is especially problematic in high-demand individuals like athletes and executives, who require rapid B12 turnover for peak physical and cognitive performance.
For my athletes, this means:
Fatigue when in the middle of training despite eating clean
Slow recovery times
Muscle soreness that lingers longer than it should
Often misdiagnosed as overtraining, when it’s actually a B12 transport issue
For my executives, this means:
Burnout symptoms despite a healthy diet and supplement stack
Brain fog in meetings
Slowed decision-making under pressure
High stress with poor stress resilience
So, what do I do since no amount of B12 pills or B12 shots can fix it?
Identify the gene: TCN2 GG or CG = higher risk for intracellular B12 deficiency.
Bypass the bottleneck by providing the right form and dose of B12:
Methylcobalamin for methylation
Adenosylcobalamin for mitochondrial energy
3. Monitor results, especially in high performers, using:
HRV
Training recovery
Mood, stress response, and cognitive clarity
And this is only the beginning of what I can do for you and your genetics. There are other genes involved with B12 such as FUT2, MTHFR, MTRR, etc, but I’ll save those for another day :)
—KB
