CYP2D6

Chr 22AR

cytochrome P450 family 2 subfamily D member 6 (gene/pseudogene)

Also known as: CPD6, CYP2D, CYP2D7AP, CYP2D7BP, CYP2D7P2, CYP2D8P2, CYP2DL1, CYPIID6

NCBI Gene: 1565 ENSG00000100197 UniProt: P10635 OMIM: 124030

This cytochrome P450 enzyme metabolizes approximately 25% of commonly prescribed drugs including antidepressants, antipsychotics, beta blockers, and antiarrhythmics, and also participates in fatty acid, steroid, and retinoid metabolism. Mutations cause drug sensitivity phenotypes including codeine sensitivity and debrisoquine sensitivity with autosomal recessive inheritance. The gene is highly polymorphic with poor metabolizers having decreased drug metabolism ability and ultrarapid metabolizers having multiple gene copies, making pharmacogenomic testing clinically important for medication dosing.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and is known to metabolize as many as 25% of commonly prescribed drugs. Its substrates include antidepressants, antipsychotics, analgesics and antitussives, beta adrenergic blocking agents, antiarrythmics and antiemetics. The gene is highly polymorphic in the human population; certain alleles result in the poor metabolizer phenotype, characterized by a decreased ability to metabolize the enzyme's substrates. Some individuals with the poor metabolizer phenotype have no functional protein since they carry 2 null alleles whereas in other individuals the gene is absent. This gene can vary in copy number and individuals with the ultrarapid metabolizer phenotype can have 3 or more active copies of the gene. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

{Codeine sensitivity}MIM #608902

{Debrisoquine sensitivity}MIM #608902

Active trials

720

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.94

LOEUF

Multiple*

Mechanism· predicted

📖

GeneReview available — CYP2D6

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.94LOEUF

pLI 0.000

Z-score -2.57

OE 1.64 (1.21–1.94)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-2.00Z-score

OE missense 1.32 (1.22–1.44)

403 obs / 304.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.64 (1.21–1.94)

0≤0.351.4

Missense OE?1.32 (1.22–1.44)

0≤0.61.4

Synonymous OE?1.43

0≤1.21.6

LoF obs/exp: 31 / 18.9Missense obs/exp: 403 / 304.9Syn Z: -3.99

Background carrier burden — how many people carry a rare variant somewhere in CYP2D6?

gnomAD v4 · ~730k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 30

781 rare PASS variants

Rare truncating (LoF)

1 in 200

111 rare PASS variants

Rare synonymous (reference)

1 in 93

374 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CYP2D6. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~555k	1 in 45	1 in 290
South Asian	~43k	1 in 26	1 in 310
Remaining (unassigned)	~30k	1 in 29	1 in 250
European (Finnish)	~27k	1 in 180	1 in 1,300
Admixed American	~22k	1 in 40	1 in 460
African / African American	~21k	1 in 33	1 in 260
East Asian	~20k	1 in 31	1 in 250
Ashkenazi Jewish	~13k	1 in 120	1 in 810
Middle Eastern	~2,882	1 in 41	1 in 320

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 9 of 9 coding exons well covered in gnomAD exomes. Genomes: 5 of 9 (exons 1, 2, 8, 9 below).? see exons ↓