rs16947 — CYP2D6 *2

CYP2D6*2 — The Most Common "Normal" Allele That Isn't Quite Normal

CYP2D6 is the enzyme behind the metabolism of roughly 25% of all prescription drugs — from antidepressants to pain medications to cancer drugs. The *2 allele, defined by the rs16947 variant (a C-to-T change causing an Arg296Cys amino acid substitution¹¹ Arg296Cys amino acid substitution
arginine to cysteine at position 296), is one of the most common CYP2D6 variants worldwide. For decades, it was classified as having "normal function," indistinguishable from the reference *1 allele. But recent research reveals a more nuanced story: this variant subtly reduces CYP2D6 expression through altered mRNA splicing, and its true impact depends heavily on what other variants accompany it on the same chromosome.

The Mechanism

The rs16947 variant alters exon 6 splicing, reducing CYP2D6 expression by at least 2-fold . The amino acid change itself (R296C) may reduce enzyme activity slightly in recombinant expression systems, but the bigger effect comes from regulatory consequences.

This SNP defines the CYP2D6*2 allele, with minor allele frequencies ranging from 17–60% across populations .

The *2 allele (rs16947) is the most frequent CYP2D6 variant in European, African, and Latino populations, though less common in East Asians where *10 predominates .

What complicates matters is that rs16947 doesn't act alone.

It's in high linkage disequilibrium with an enhancer SNP (rs5758550) located over 100 kb downstream .

The enhancer SNP increases CYP2D6 expression 2-fold, while rs16947 reduces it by 0.5-fold; haplotypes containing both variants show near-normal activity . This means that a person with two copies of the T allele at rs16947 could have anywhere from reduced to increased enzyme activity depending on the larger haplotype context — something standard genotyping panels often miss.

The Evidence

The landmark discovery came from a 2014 study²² The landmark discovery came from a 2014 study
Wang et al. Common CYP2D6 polymorphisms affecting alternative splicing and transcription. Human Molecular Genetics, 2014 that used allelic expression analysis in human liver samples.

In a pediatric cohort of 164 individuals, rs16947 alone was associated with reduced CYP2D6 metabolic activity measured by dextromethorphan ratios .

Overall allele frequencies harboring rs16947 and/or the enhancer SNP range from 17% in East Asians to 67% in Africans .

A 2019 follow-up study³³ A 2019 follow-up study
Ray et al. CYP2D6 haplotypes with enhancer SNP rs5758550 and rs16947. Pharmacogenetics and Genomics, 2019 tested the haplotype-phenotype relationship in 122 human liver microsomes.

Haplotypes containing both rs5758550 and rs16947 convey normal or slightly increased enzyme activity , supporting the idea that CYP2D6 enzyme function depends on the full haplotype, not single variants in isolation.

Despite this mechanistic evidence,

CPIC currently classifies CYP2D6*2 as having normal function , assigning it an activity score of 1.0 — the same as the reference *1 allele. This classification drives dosing guidelines for dozens of drugs, but may oversimplify for individuals whose *2 allele lacks the compensatory enhancer variant.

Practical Implications

If your 23andMe report shows the T allele at rs16947, you carry at least one copy of CYP2D6*2.

Between 43–67% of individuals have two normal-function alleles (*1 or *2) or one normal plus one decreased-function allele, resulting in normal metabolizer status . However, there is large variability in drug response within individuals genotyped as normal metabolizers, and the causes of this variation are unknown

— the *2/*enhancer haplotype interaction is a leading candidate explanation.

CYP2D6 is responsible for metabolizing many commonly prescribed drugs including antidepressants, antipsychotics, analgesics, and beta-blockers .

Pharmacogenomic clinical guidelines for at least 48 CYP2D6-substrate drugs have been developed by CPIC and other consortia. For CYP2D6*2 specifically, current guidelines treat it as normal-function and don't recommend dose adjustments. But if you experience unexpected side effects or lack of efficacy with a CYP2D6-substrate drug, the nuanced function of your *2 allele — especially if not accompanied by the enhancer — could be relevant.

The challenge is that consumer genetic tests like 23andMe typically only report rs16947 itself, not the distant enhancer SNP or the full haplotype structure. Without phased haplotype information, knowing you have *2 tells you less than it should. Clinical pharmacogenetic testing that includes copy number analysis and structural variant detection provides a more complete picture.

Interactions

The rs16947 variant interacts significantly with rs5758550 (enhancer SNP). Individuals who carry rs16947 (T allele) on a haplotype that also has rs5758550 (G allele) tend to have near-normal or slightly elevated CYP2D6 activity. Those with rs16947 but without the enhancer may have moderately reduced activity. This is a case where compound genotyping across a >100 kb span matters more than the single-SNP result.

Additionally, rs16947 defines several star alleles beyond *2, including *29, *17, *35, and others that carry additional functional variants. The *41 allele contains both rs16947 and the splicing-defect variant rs28371725, resulting in clearly reduced function. Because rs16947 is so common and appears in many haplotype backgrounds, interpreting it requires knowing what else is present on that chromosome.

For compound heterozygotes — individuals with one *2 allele and one reduced/no-function allele like *4, *5, or *10 — the impact depends on whether the *2 carries the enhancer. A *2 (with enhancer) plus *4 diplotype might behave like a normal metabolizer, while *2 (without enhancer) plus *4 could trend toward intermediate metabolism.