rs373489637 — CYP2B6 V183G

Near-complete loss-of-function CYP2B6 variant causing severely impaired metabolism of efavirenz, bupropion, methadone, and other CYP2B6 substrates

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CYP2B6 V183G — A Rare Loss-of-Function Variant Identified in African Populations

CYP2B6 is one of the most polymorphic drug-metabolizing enzymes in the human genome, responsible for the metabolism of approximately 8% of prescription medications including critical drugs for HIV treatment, pain management, depression, and cancer therapy. The V183G variant (c.548T>G, p.Val183Gly) is a rare missense mutation first identified in a Rwandan population study that results in near-complete loss of CYP2B6 enzymatic function. Carriers of this variant — even one copy — face significantly elevated drug plasma concentrations and toxicity risk when prescribed standard doses of CYP2B6-metabolized medications.

The Mechanism

At position 183 in the CYP2B6 protein, a valine residue is replaced by glycine. Valine is a branched-chain amino acid with a hydrophobic side chain, while glycine is the smallest amino acid with no side chain at all. Radloff et al. (2013)11 Radloff et al. (2013)
Novel CYP2B6 enzyme variants in a Rwandese population: functional characterization and assessment of in silico prediction tools demonstrated through recombinant expression in COS-1 cells that this substitution causes "complete or almost complete loss-of-function" for both bupropion hydroxylation and efavirenz metabolism. Molecular docking analyses revealed that V183G produces conformational changes within the enzyme's active site that abolish substrate binding and catalysis. This is in sharp contrast to the common CYP2B6*6 (516G>T) variant, which reduces activity by roughly 70% — V183G effectively eliminates it entirely.

The Evidence

The V183G variant was discovered by Radloff et al. (2013)22 Radloff et al. (2013) in the course of sequencing the CYP2B6 gene in a Rwandan population. Of eight novel nonsynonymous variants identified, V183G was among four classified as near-complete loss-of-function (alongside p.G110V, p.I114T, and p.F213L). The variant was assigned one of five new star allele designations (CYP2B6*33–*37). The finding highlights the pharmacogenomic diversity of African populations, which are underrepresented in global databases — the G allele frequency in the ALFA database is 0.000 across 660 global samples, yet this variant has clinical significance for the populations in which it does occur.

For efavirenz, the drug most directly relevant to this variant, CPIC guidelines33 CPIC guidelines provide Level A evidence that CYP2B6 poor metabolizer status is associated with 3–4 fold higher plasma concentrations, significantly increased CNS adverse effects (dizziness, insomnia, vivid dreams, confusion, suicidal ideation), and elevated risk of treatment discontinuation. While CPIC guidelines were primarily developed based on the common CYP2B6*6 allele, a complete loss-of-function variant like V183G would be expected to confer at least equivalent, likely greater, risk.

The clinical significance of CYP2B6 poor metabolizer status for sub-Saharan African populations is underscored by the observation from Swart et al. (2013)44 Swart et al. (2013) that CYP2B6 genotype strongly predicts efavirenz plasma levels in South African HIV/AIDS patients, with CYP2B6*6/*6 homozygotes showing 97% specificity for supratherapeutic efavirenz concentrations. A complete loss-of-function variant compounds this pharmacokinetic vulnerability.

Practical Implications

For efavirenz-based HIV treatment — the primary clinical context where this variant matters — heterozygous carriers (GT) will experience moderately elevated drug exposure and CNS toxicity risk. For any person identified as homozygous (GG, extremely rare), standard efavirenz dosing would be contraindicated, with alternative antiretrovirals strongly preferred per CPIC guidance.

Bupropion, a prodrug requiring CYP2B6 conversion to its active metabolite hydroxybupropion, would be expected to show reduced antidepressant and smoking cessation efficacy in carriers. Methadone clearance would be markedly reduced, raising risk of QT prolongation and respiratory depression. These implications apply to all CYP2B6 poor metabolizers, regardless of the specific variant responsible.

Interactions

V183G is a standalone loss-of-function allele. It can theoretically occur in combination with other CYP2B6 reduced-function alleles (such as the common CYP2B6*6 allele defined by rs3745274), which would compound metabolic impairment further. The overall CYP2B6 metabolizer phenotype assigned in clinical practice is based on the combination of all alleles carried; a V183G allele in combination with any other reduced-function allele would result in poor or ultrarapid metabolizer classification depending on the combination. CYP2B6 activity is also inducible by rifampin and efavirenz itself; in patients on combination antiretroviral regimens, drug-drug interactions can partially modulate but not overcome the genetic deficiency.

Drug Interactions

efavirenz increased_toxicity CPIC
bupropion reduced_efficacy literature
methadone dose_adjustment literature
cyclophosphamide dose_adjustment literature
ketamine dose_adjustment literature

Genotype Interpretations

What each possible genotype means for this variant.

TT Normal Metabolizer Normal

Normal CYP2B6 function — standard drug metabolism

You have two copies of the normal CYP2B6 reference allele at this position. Your CYP2B6 enzyme functions at full capacity for this variant, and standard prescribed doses of efavirenz, bupropion, methadone, and other CYP2B6-metabolized drugs are appropriate. The vast majority of people worldwide carry this genotype; the V183G variant is extremely rare in global databases and was primarily identified in a Rwandan population study.

GT Intermediate/Poor Metabolizer Intermediate

One copy of the near-complete loss-of-function V183G allele — meaningfully reduced CYP2B6 activity

The V183G substitution (valine → glycine at position 183) abolishes CYP2B6 catalytic activity from that allele as demonstrated by recombinant protein expression studies. Your overall phenotype depends on your second CYP2B6 allele: if that allele is wild-type, you are functionally an intermediate metabolizer (one functional allele, one nonfunctional). If your second allele also carries a reduced-function variant (such as the common 516G>T), you may be classified as a poor metabolizer. For efavirenz, intermediate metabolizers typically show 1.5–2 fold elevated plasma concentrations compared to normal metabolizers; with V183G-driven complete loss on one allele, the elevation may approach poor metabolizer ranges.

GG Homozygous Loss-of-Function Poor

Two copies of the V183G loss-of-function allele — near-complete absence of CYP2B6 activity

With both alleles carrying the V183G substitution, your CYP2B6 enzyme is essentially nonfunctional. Recombinant expression studies of V183G show complete or near-complete loss of catalytic activity toward both efavirenz and bupropion. For efavirenz, plasma concentrations in poor metabolizers are typically 3–4 fold higher than in normal metabolizers; with complete loss of function on both alleles, this elevation may be even more pronounced. CPIC guidelines recommend considering alternatives to efavirenz for poor metabolizers; with homozygous V183G, alternative antiretrovirals are strongly preferred. For methadone, the risk of lethal accumulation is high. For bupropion, therapeutic efficacy would likely be minimal. Inform all prescribers before starting any new medications.