CYP2D6 Cytochrome P450 2D6
CYP2D6 metabolises around a quarter of all prescribed drugs, among them codeine, tramadol, tamoxifen, many antidepressants and antipsychotics, and some beta-blockers.
What does CYP2D6 do?
CYP2D6 metabolises around a quarter of all prescribed drugs, among them codeine, tramadol, tamoxifen, many antidepressants and antipsychotics, and some beta-blockers. It is the most polymorphic of the drug-metabolising enzymes: more than 100 star alleles are described, whole-gene deletions and duplications are common, and activity ranges from none to several times normal. Codeine is the classic example — the enzyme turns it into morphine, so poor metabolisers get little pain relief and ultrarapid metabolisers can be harmed by a standard dose.
What do the CYP2D6 metaboliser phenotypes mean?
Each person carries two CYP2D6 alleles. Each allele has a function and an activity score; the two scores are added and the total is mapped to a phenotype as follows.
| Phenotype | How it is assigned | What it means |
|---|---|---|
| Ultrarapid Metabolizer | activity score > 2.25 | Gene duplication or multiple increased-function alleles: unusually fast metabolism. |
| Normal Metabolizer | activity score 1.25 – 2.25 | The reference range of enzyme activity. |
| Intermediate Metabolizer | activity score 0.25 – 1 | Reduced enzyme activity. |
| Poor Metabolizer | activity score 0 | No functional enzyme. |
Which CYP2D6 star alleles are there, and how common are they?
| Allele | Function | Activity score | Defining variants | Frequency (EUR / EAS / AFR / SAS / AMR) | Note |
|---|---|---|---|---|---|
| *1 | normal function | 1 | reference | 35.0% / 25.0% / 30.0% / 35.0% / 35.0% | Wild-type/reference allele. Normal enzyme activity. |
| *2 | normal function | 1 | rs16947 2850C>T (R296C) rs1135840 4180G>C (S486T) | 27.0% / 12.0% / 20.0% / 25.0% / 25.0% | Normal function allele. Common variant with normal enzyme activity. Shared SNPs with many other alleles (*8, *11, *12, *14, *17, *29, *41). |
| *3 | no function | 0 | rs35742686 2549delA (frameshift) | 1.0% / 0.1% / 0.5% / 0.5% / 0.5% | Loss-of-function allele. Frameshift mutation leading to premature stop codon. More common in Europeans. |
| *4 | no function | 0 | rs3892097 1846G>A (splicing defect) rs1065852 100C>T (P34S) | 20.0% / 1.0% / 6.0% / 10.0% / 12.0% | Most common loss-of-function allele in Europeans (~20%). Splicing defect abolishes enzyme activity. Much less common in East Asians (~1%). |
| *6 | no function | 0 | rs5030655 1707delT (frameshift) | 1.0% / 0.1% / 0.5% / 0.5% / 0.5% | Loss-of-function allele. Frameshift mutation. |
| *7 | no function | 0 | rs5030867 2935A>C (H324P) | 0.1% / 0.1% / 0.1% / 0.1% / 0.1% | Rare loss-of-function allele. Missense mutation H324P. |
| *8 | no function | 0 | rs5030865 1758G>T (G169X stop) rs16947 2850C>T (R296C) | 0.1% / 0.1% / 0.1% / 0.1% / 0.1% | Rare loss-of-function allele. Premature stop codon. |
| *10 | decreased function | 0.25 | rs1065852 100C>T (P34S) rs1135840 4180G>C (S486T) | 2.0% / 45.0% / 5.0% / 15.0% / 8.0% | Most common decreased function allele in East Asians (40-50%). Unstable protein with reduced activity. Major contributor to intermediate metabolizer phenotype in Asian populations. |
| *17 | decreased function | 0.5 | rs28371706 1023C>T (T107I) rs16947 2850C>T (R296C) | 0.1% / 0.1% / 20.0% / 0.5% / 3.0% | Decreased function allele, predominantly in African populations (~20%). Substrate-dependent reduced activity. |
| *29 | decreased function | 0.5 | rs59421388 1659G>A (V136I) rs16947 2850C>T (R296C) | 0.1% / 0.1% / 10.0% / 0.5% / 2.0% | Decreased function allele, predominantly in African populations (~10%). |
| *41 | decreased function | 0.5 | rs28371725 2988G>A (splicing defect) rs16947 2850C>T (R296C) | 9.0% / 2.0% / 4.0% / 8.0% / 6.0% | Decreased function allele. Splicing defect reduces but does not abolish activity. Relatively common in Europeans and South Asians. |
Which drugs does CYP2D6 affect?
- Codeine Opioid Analgesic CPIC level A
- Codeine only relieves pain after CYP2D6 turns it into morphine. Poor metabolisers get little effect; ultrarapid metabolisers can produce dangerous morphine levels from a standard dose, which is why codeine is contraindicated in children after tonsillectomy.
- Tramadol Opioid Analgesic CPIC level A
- Tramadol's main analgesic effect comes from its CYP2D6 metabolite O-desmethyltramadol. As with codeine, poor metabolisers get reduced analgesia and ultrarapid metabolisers risk toxicity.
- Tamoxifen Selective Estrogen Receptor Modulator CPIC level A
- Tamoxifen is activated by CYP2D6 into endoxifen, its most potent anti-oestrogen metabolite. Poor metabolisers have lower endoxifen levels, and several studies associate this with a higher breast-cancer recurrence rate.
- Atomoxetine ADHD Medication CPIC level A
- Atomoxetine, an ADHD medicine, is cleared by CYP2D6. Poor metabolisers have several-fold higher exposure, with more cardiovascular and other side effects, and typically need lower doses.
- Ondansetron Antiemetic CPIC level B
- Ondansetron is inactivated by CYP2D6. Ultrarapid metabolisers clear it quickly and have a higher rate of breakthrough nausea and vomiting, so an alternative antiemetic is suggested.
Can a 23andMe or AncestryDNA file tell you your CYP2D6 type?
Consumer DNA chips read single-nucleotide changes but cannot see gene deletions (*5) or duplications (*1xN, *2xN), which are exactly what defines many poor and ultrarapid metabolisers. A CYP2D6 call from chip data is therefore a lower-confidence estimate than for CYP2C19 or CYP2C9, and Orviva reports it with that caveat.
Upload your 23andMe, AncestryDNA or WeGene raw file → · Ask G2: “What is my CYP2D6 metaboliser status and which of my medicines does it affect?”
Genetic associations describe risk across populations, not a diagnosis for any one person. Most variants shift risk modestly and act alongside lifestyle, environment and other genes. Consumer DNA chips do not read every position and can be wrong at any single one. For general education only; talk to a clinician or genetic counsellor before acting on anything here, and never change a prescribed medicine without your prescriber.