rs373489637 — CYP2B6 V183G

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.