CYP3A5: the gene where being a normal metabolizer is the unusual result
CYP3A5 is the one page in this set where the labels run backwards from expectation. The genotype CPIC calls poor metabolizer is the one most Europeans have, and the one that gets the standard dose.
Also known as: cytochrome P450 3A5.
What CYP3A5 does
The enzyme is a relative of CYP3A4 and works on many of the same drugs, but unlike CYP3A4 most people do not make a functioning version of it. A variant called *3 introduces a splicing change that prevents working enzyme from being produced, and it is the common allele in European populations. People who carry a functional copy, described as expressers, have an extra route of clearance that most of their neighbours lack. For tacrolimus, which has a narrow therapeutic window, that extra route changes the dose needed to reach target.
The metabolizer groups
CPIC grades CYP3A5 as normal, intermediate or poor metabolizer, with possible intermediate metabolizer and Indeterminate for combinations that cannot be graded cleanly. Read the labels carefully here. Normal and intermediate metabolizer both mean the person expresses functional enzyme and clears tacrolimus faster than average, so both get the increased starting dose. Poor metabolizer means no functional enzyme, which is the common state and the one the standard dose was built around. How often the functional allele turns up differs markedly between ancestries, so the same result carries a different prior probability depending on where your ancestors came from.
Medications where it matters
tacrolimus (Prograf, Advagraf)
Tacrolimus prevents rejection after a solid-organ transplant and has very little room between too little and too much. Expressers clear it faster and are less likely to reach the target blood level on a standard starting dose, which is why the guidance raises the starting dose for them and caps how far. Every version of the recommendation ends in therapeutic drug monitoring, because the blood level is what actually governs the dose.
| If your result is | Published CPIC guidance |
|---|---|
| Intermediate Metabolizer | Per CPIC (A): "Increase starting dose 1.5 to 2 times recommended starting dose. Total starting dose should not exceed 0.3 mg/kg/day. Use therapeutic drug monitoring to guide dose adjustments." |
| Normal Metabolizer | Per CPIC (A): "Increase starting dose 1.5 to 2 times recommended starting dose. Total starting dose should not exceed 0.3 mg/kg/day. Use therapeutic drug monitoring to guide dose adjustments." |
| Poor Metabolizer | Per CPIC (A): "Initiate therapy with standard recommended dose. Use therapeutic drug monitoring to guide dose adjustments." |
| Possible Intermediate Metabolizer | Per CPIC (A): "Increase starting dose 1.5 to 2 times recommended starting dose. Total starting dose should not exceed 0.3 mg/kg/day. Use therapeutic drug monitoring to guide dose adjustments." |
Is this in your raw DNA file?
CYP3A5 is not part of the standard chip or variant-file report. It is a Deep Read gene, read from aligned reads in a BAM or CRAM file. This is also a gene where a consumer re-analysis is background reading rather than a clinical input: tacrolimus dosing after a transplant is driven by blood-level monitoring from the first days of treatment, and any genotype-informed starting dose comes from the transplant service's own testing. Where the reads do not resolve the diplotype, the result is Indeterminate.
A genotyping chip reads only a few hundred thousand pre-selected positions, about 0.02% of your genome, chosen for common variation. It does not sequence the rest, so it cannot find the rare or novel pathogenic variants the clinical and carrier modules look for: a “no finding” from chip data means “this chip never looked”, far more so than with whole-genome sequencing. Chip data suits common-variant traits, pharmacogenomic tag SNPs, and haplogroup ancestry, not clinical or carrier screening.
Common questions
Why does poor metabolizer sound bad but get the standard dose?
Because the naming convention describes enzyme activity, not desirability. Poor metabolizer here means no functional CYP3A5, which is the common state and the state the standard dosing was calibrated on. The unusual result is being an expresser.
Is CYP3A5 in my 23andMe or AncestryDNA raw data?
The main *3 position appears on some arrays, but Aimosti reads this gene from aligned reads as part of the Deep Read panel rather than from a chip file, and reports Indeterminate where the diplotype does not resolve.
I am waiting for a transplant. Is this worth doing?
Not as a substitute for anything. The transplant service will run its own testing and will dose from blood levels regardless. Knowing your status ahead of time may make the first conversation shorter, and that is the honest extent of it.