rs17002852 — CYP2D6

The CYP2D6 Genotyping Blind Spot

About 25% of all prescription medications are processed by the CYP2D6 enzyme — a figure that spans everything from opioids like codeine and tramadol to antidepressants, antipsychotics, beta-blockers, and tamoxifen. Accurate genotyping of CYP2D6 is therefore one of the highest-stakes tasks in clinical pharmacogenomics. The rs17002852 variant sits in a unique position: it doesn't alter CYP2D6 enzyme function directly, but it can disrupt the diagnostic tools used to read your CYP2D6 status — specifically the detection of the CYP2D6*3 non-functional allele.

The Mechanism

CYP2D6 is located on chromosome 22 (minus strand), and rs17002852 corresponds to a synonymous change¹¹ synonymous change
NM_000106.6:c.696T>C; plus-strand A>G at chr22:42128321 (GRCh38) at codon 696 of the CYP2D6 transcript. The amino acid at position 232 (histidine) remains unchanged — so enzyme structure and activity are unaffected by this variant alone.

The problem arises in the laboratory. Standard hydrolysis probe assays and pyrosequencing assays for CYP2D6*3 (rs35742686)²² CYP2D6*3 (rs35742686)
*3 is a frameshift deletion that abolishes CYP2D6 function are designed around the assumption that the nucleotide at the g.2470 position (rs17002852) is the common reference (A on the plus strand, T on the coding strand). When the G allele is present at rs17002852, its proximity to the *3 detection probe causes allele dropout³³ allele dropout
Allele dropout: one allele in a heterozygous sample fails to amplify or be detected, producing a false homozygous result — the affected allele is simply not detected. A person who carries CYP2D6*3 on the same chromosome as rs17002852 G may appear homozygous normal on standard assays, when they are actually a CYP2D6*3 heterozygote or compound heterozygote.

The Evidence

Scantamburlo et al. (2017)⁴⁴ Scantamburlo et al. (2017)
Allele Drop Out Conferred by a Frequent CYP2D6 Genetic Variation. Cell Physiol Biochem, 43:2297–2309. genotyped 365 patient samples using three parallel methods — Sanger sequencing (gold standard), hydrolysis probe assays, and pyrosequencing. A discrepancy emerged for CYP2D6*3 detection in one sample that also carried rs17002852. The G allele frequency was 2.47% in this cohort, consistent with the global ALFA frequency of 0.74% and higher frequencies observed in Ashkenazi Jewish (~1.7%) and South Asian (~1.8%) populations. The solution was assay redesign to avoid the g.2470 position. The authors recommend intra-patient validation with at least two independent methods when rs17002852 is detected, as any single-method CYP2D6 panel may silently miss a co-inherited *3 or other nearby non-functional allele.

ClinVar records the A>G variant VCV000828876⁵⁵ VCV000828876
ClinVar drug response classification, single submission, no assertion criteria under a "drug response" classification related to tramadol metabolism — reflecting that misclassification of *3 carrier status would affect tramadol prescribing decisions, since CYP2D6*3 carriers have reduced conversion of tramadol to its active O-desmethyltramadol metabolite.

Practical Actions

Most people carrying the G allele at rs17002852 will never know they have it, and this variant itself does not change how medications work in the body. The actionable implication applies when you are undergoing CYP2D6 genotyping for clinical or pharmacogenomic purposes: standard single-method panels may miss a co-inherited CYP2D6*3 allele. If your genotyping results show this variant alongside CYP2D6*3 detection, or if you are prescribed medications with narrow therapeutic windows where CYP2D6 status matters (tramadol, codeine, tamoxifen, tricyclic antidepressants), confirmatory testing with an alternative method such as next-generation sequencing or a redesigned assay is warranted.

Interactions

This variant's clinical relevance is entirely defined by its interaction with the CYP2D6*3 allele (rs35742686). The rs17002852 G allele can occur in trans (on the opposite chromosome) from CYP2D6*3, or in cis (on the same chromosome), either combination causing the same diagnostic assay problem. Users who carry both rs17002852 G and a CYP2D6 non-functional allele on standard panels should confirm their complete CYP2D6 status with extended genotyping. See also rs3892097 (*4) and rs1065852 (*10) for the full CYP2D6 picture.