rs28371725 — CYP2D6 *41

Intronic splice variant causing decreased CYP2D6 enzyme activity through aberrant splicing

See your personal result for CYP2D6

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

CYP2D6*41 — One of the Most Common Intermediate Metabolizer Alleles

The CYP2D6 enzyme metabolizes approximately 25% of all prescribed drugs, including pain medications, antidepressants, antipsychotics, and some cardiovascular drugs.

CYP2D6 is involved in the metabolism of a wide range of medications including drugs for pain management, cancer, mental health disorders, some cardiovascular symptoms . The CYP2D6*41 allele is defined by an intronic variant (2988G>A, also known as c.985+39G>A) that disrupts normal splicing patterns, resulting in increased levels of a nonfunctional splice variant lacking exon 6 and up to 2.9-fold less functional transcript .

CYP2D6*41 has allele frequencies of 4% to 11.5% among individuals of African ancestry, 2% to 12% in Asian populations, and approximately 9% in Europeans .

The allele is particularly prevalent in Arabian Peninsula countries, with frequencies reaching 18.4% in Saudi Arabia and 15.2% in the United Arab Emirates . This makes *41 one of the most common decreased-function CYP2D6 alleles worldwide, contributing to the intermediate metabolizer phenotype in approximately 10-15% of Caucasians 11 carriers typically have one *41 allele paired with a normal-function allele.

The Mechanism

The 2988G>A variant sits in intron 6, 39 base pairs downstream from exon 6.

This intronic change is associated with increased levels of a nonfunctional splice variant lacking exon 6 . The aberrant splicing shifts the balance of transcripts away from the functional full-length mRNA toward a version that cannot produce active enzyme. Studies have shown that

*41 carriers have up to 7.3-fold increased levels of the splice variant and up to 2.9-fold less functional transcript .

The Evidence

The CPIC guideline assigns the *41 allele an activity score of 0.5, classifying individuals with one *41 allele paired with a normal-function allele as intermediate metabolizers (activity score 1.0) 22 and homozygous *41/*41 individuals as intermediate metabolizers (activity score 1.0).

Clinical evidence from multiple substrates confirms reduced drug metabolism in *41 carriers. For codeine and tramadol, which require CYP2D6 activation to produce their active metabolites (morphine and O-desmethyltramadol), *41 carriers experience reduced analgesia. Conversely, for drugs directly inactivated by CYP2D6 (paroxetine, fluvoxamine, venlafaxine), *41 carriers have higher parent drug concentrations and increased risk of side effects.

Practical Implications

If you carry one or two copies of the *41 allele, your CYP2D6 enzyme activity is reduced but not absent. This has bidirectional clinical implications depending on whether the drug is a prodrug requiring activation or a parent drug requiring inactivation.

For prodrugs (codeine, tramadol, tamoxifen): *41 carriers produce less active metabolite, which can lead to treatment failure. CPIC recommends avoiding codeine and tramadol in intermediate metabolizers, or using alternative opioids not metabolized by CYP2D6 (morphine, hydromorphone, oxymorphone, fentanyl) 33 as these do not require CYP2D6 activation.

For drugs inactivated by CYP2D6 (most antidepressants, antipsychotics): *41 carriers accumulate higher drug levels. For paroxetine and fluvoxamine, CPIC recommends considering a 50% dose reduction or selecting an alternative SSRI not extensively metabolized by CYP2D6 (sertraline at standard doses, citalopram, escitalopram).

Drug-drug interactions are particularly important for *41 carriers. Strong CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion, quinidine) can push an intermediate metabolizer into poor metabolizer territory through phenoconversion.

Interactions

CYP2D6 metabolism is determined by the combination of both alleles. Individuals with *41 paired with a no-function allele (*3, *4, *5, *6) typically have activity scores of 0.5 and are classified as intermediate metabolizers, though they may function closer to poor metabolizers for some substrates. When *41 is paired with another decreased-function allele like *10, the combined reduction can significantly impair drug metabolism. Conversely, *41 paired with a gene duplication (*1xN, *2xN) can restore activity closer to normal metabolizer levels.

The *41 haplotype usually contains both rs28371725 (the splice defect) and rs16947 (R296C, defining *2). Clinical interpretation requires assessment of the full CYP2D6 diplotype, not single SNPs in isolation.

Drug Interactions

codeine reduced_efficacy CPIC
tramadol reduced_efficacy CPIC
tamoxifen reduced_efficacy CPIC
venlafaxine increased_toxicity DPWG
paroxetine increased_toxicity CPIC
fluvoxamine increased_toxicity CPIC
atomoxetine increased_toxicity CPIC
aripiprazole dose_adjustment CPIC
risperidone dose_adjustment CPIC

Genotype Interpretations

What each possible genotype means for this variant.

CC Normal Metabolizer Normal

Normal CYP2D6 enzyme activity

You have two copies of the normal C allele at this position. This means you do not carry the CYP2D6*41 splice defect and have normal CYP2D6 enzyme activity (assuming no other decreased-function or no-function variants elsewhere in the gene). About 81% of people share this genotype. Your CYP2D6 enzyme produces normal amounts of functional protein, allowing you to metabolize CYP2D6 substrate drugs at a typical rate.

CT Intermediate Metabolizer Intermediate

Moderately reduced CYP2D6 enzyme activity

The CYP2D6*41 allele contains an intronic variant that disrupts normal mRNA splicing, causing a portion of your CYP2D6 transcripts to skip exon 6 and produce nonfunctional protein. With one functional allele remaining, you maintain partial enzyme activity—enough to avoid being classified as a poor metabolizer, but reduced enough to cause clinically meaningful differences in drug response. The exact degree of reduction varies by substrate and can be influenced by drug-drug interactions. Strong CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion) can push you into poor metabolizer territory through phenoconversion.

TT Intermediate Metabolizer Reduced

Significantly reduced CYP2D6 enzyme activity

With both alleles affected by the 2988G>A splice variant, a substantial portion of your CYP2D6 mRNA undergoes aberrant splicing, skipping exon 6 and producing nonfunctional protein. While you are not a complete poor metabolizer (you do produce some functional enzyme), your reduced activity has clinically significant consequences for many drugs. You are also highly susceptible to phenoconversion (being pushed into poor metabolizer territory) by CYP2D6 inhibitor drugs.