CYP2D6 *4
part of CYP2D6 Cytochrome P450 Nomenclature DB Haplotype Set

Clinical Annotations

Clinical Variants that meet the highest level of criteria, manually curated by PharmGKB, are shown below. Please follow the link in the "Position" column for more information about a particular variant. Each link in the "Position" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications can be found on the Variant Page.

To see more Clinical Variants with lower levels of criteria, click the button at the bottom of the table.

Clinical Annotation for CYP2D6*1, CYP2D6*10, CYP2D6*1xN, CYP2D6*2, CYP2D6*2xN, CYP2D6*3, CYP2D6*4, CYP2D6*5, CYP2D6*6, nortriptyline and Depressive Disorder, Major (level 1A Efficacy, Toxicity/ADR, Metabolism/PK)

Level of Evidence
Level 1A
Efficacy, Toxicity/ADR, Metabolism/PK
*1, *10, *1xN, *2, *2xN, *3, *4, *5, *6
Depressive Disorder, Major
OMB Race
Mixed Population
Race Notes
Asian, Mixed, and White

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Disclaimer: The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision-making and to identify questions for further research. New evidence may have emerged since the time an annotation was submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or diseases that are not specifically identified.

The annotations do not account for individual variations among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the PharmGKB clinical annotations, or for any errors or omissions.

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HGVS representation NC_000022.10:g.[42522613C>G;42524947C>T;42525132C>G;42525798G>C;42525811T>C;42525821G>T;42526694G>A]
Translation Table This haplotype is part of the set "CYP2D6 Cytochrome P450 Nomenclature DB Haplotype Set". There is a full translation table for CYP2D6 Cytochrome P450 Nomenclature DB Haplotype Set

Download Translation Table


Any chromosomal positions listed below are assumed to be on the GRCh38 assembly. Be aware, the assembly may differ for variants elsewhere on the PharmGKB site.

Variant Location Allele Reference Allele
rs1065852 A G
rs28371703 T G
rs28371704 C T
rs28371705 C G
rs1058164 G C
rs3892097 T C
rs1135840 G C

Variant Annotations

Haplotype Annotations

PharmGKB haplotype annotations provide information about haplotype-drug pairs based on individual PubMed publications. Each annotation represents information from a single paper and the goal is to report the information that the author states, not an interpretation of the paper. The PMID for supporting PubMed publications is found in the "Evidence" field.

Information presented, including study size, allele frequencies and statistics is taken directly from the publication. However, if the author does not correct p-values in cases of multiple hypotheses, curators may apply a Bonferroni correction. Curators attempt to report study size based on the actual number of participants used for the calculation of the association statistics, so the number may vary slightly from what is reported in the abstract of the paper. OMB Race Category information is derived from the paper and mapped to standardized categories. Category definitions may be found by clicking on the "OMB Race Category" link.

List of all variant annotations for CYP2D6*4

There are direct annotations for this haplotype. Register or sign in to see them.

VIP Annotation

CYP2D6*4 [Articles:2211621, 1978251, 1978565] is a non-functional haplotype that contributes to the majority of PMs observed in Caucasian populations [Article:17301689]. This allele has achieved a very high frequency (see allele frequency table), and homozygous individuals are common [Article:17301689]. These individuals are at increased risk when compared to their EM counterparts for toxicities or lack of efficacy due to CYP2D6 inactivity [Article:16968950]. For example, in situations in which the drug that is given needs to be converted to an active metabolite before some phenotypic effect is observed (such as the conversion of codeine to morphine by CYP2D6 [Article:9352573]), individuals possesing a PM phenotype (most commonly caused by CYP2D6*4, although also caused by CYP2D6*3, CYP2D6*5, and CYP2D6*6) will face a lack of efficacy. Another potential adverse effect can result from high concentrations of parent drug that may build up in individuals who are PMs that is not seen in their EM counterparts, who are quickly able to reduce concentrations of parent drug by CYP2D6 metabolism [Articles:16958828, 16968950].

Allele frequency table

European Caucasian
.33-.36.22-.33.01-.04.12-.21.02-.07.010-.02.01-.020N/DN/D.02[Articles:9241659, 9012401, 1681816, 7909282, 7697944, 9511177]
US Caucasian
.36-.40.26-.37.01-.02.18-.23.02-.05.01.02-.03.02-.080N/DN/D.01[Articles:8098046, 9918137, 10634130, 11505219]
African American
.29-.35.18-.270.06-.08.06-.0700.03-.08.15-.23N/DN/D.01-.05[Articles:9918137, 11505219, 12152006, 8098046]
Japanese.42-.43.09-.12N/D.01.05-.06N/DN/D.38-.41N/DN/DN/DN/D[Articles:10886115, 10975611, 10340923]
ZimbabweanN/DN/D0.02-.03.04N/D0.06.34N/DN/DN/D[Articles:7908586, 8911874]
Tanzanian.[Articles:10634133, 11470994, 11372584]
Amerindian.66.190.04-.[Articles:10376769, 9731721]
Subsaharan Africa
North Africa
Middle Eastern
Central/South Asia
East Asia
Native American
Key Publications:
  1. CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure. Pharmacogenetics and genomics. 2007. Sistonen Johanna, Sajantila Antti, Lao Oscar, Corander Jukka, Barbujani Guido, Fuselli Silvia. PubMed
  2. Pharmacogenetics, drug-metabolizing enzymes, and clinical practice. Pharmacological reviews. 2006. Gardiner Sharon J, Begg Evan J. PubMed
  3. CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxine. Journal of clinical pharmacy and therapeutics. 2006. Shams M E E, Arneth B, Hiemke C, Dragicevic A, Müller M J, Kaiser R, Lackner K, Härtter S. PubMed
  4. Genetically deficient CYP2D6 metabolism provides protection against oral opiate dependence. Pharmacogenetics. 1997. Tyndale R F, Droll K P, Sellers E M. PubMed
  5. The human CYP2D locus associated with a common genetic defect in drug oxidation: a G1934----A base change in intron 3 of a mutant CYP2D6 allele results in an aberrant 3' splice recognition site. American journal of human genetics. 1990. Hanioka N, Kimura S, Meyer U A, Gonzalez F J. PubMed
  6. Identification of the primary gene defect at the cytochrome P450 CYP2D locus. Nature. 1990. Gough A C, Miles J S, Spurr N K, Moss J E, Gaedigk A, Eichelbaum M, Wolf C R. PubMed
  7. Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolizers of debrisoquine. Study of the functional significance of individual mutations by expression of chimeric genes. The Journal of biological chemistry. 1990. Kagimoto M, Heim M, Kagimoto K, Zeugin T, Meyer U A. PubMed
Drugs / Other Molecules
Diseases Cystic Fibrosis Depression Hypertension Neoplasms Pain Parkinson Disease Schizophrenia


How many SNPs, indels, repeats define this haplotype?CYP2D6 haplotypes are typically determined by a genotyping algorithm.  For the purposes of this VIP, we will define the SNPs that make up a haplotype from those SNPs which have variant pages.  For fully defined CYP2D6 haplotypes, please see http://www.cypalleles.ki.se/cyp2d6.htm

CYP2D6*4 includes CYP2D6 100C>T (rs1065852) and CYP2D6 1846G>A (rs3892097)