rs6413419 — CYP2E1 *4 (V179I)

CYP2E1*4 (Val179Ile) — A Rare Variant Affecting the Body's Chemical Detoxification Enzyme

CYP2E1 (cytochrome P450 2E1) is the liver's front-line enzyme for metabolising a surprisingly diverse set of molecules — from the pain reliever in your medicine cabinet to the alcohol in a glass of wine, the anaesthetic gases used in surgery, and the industrial chemicals benzene and carbon tetrachloride. CYP2E1 is constitutively expressed¹¹ CYP2E1 is constitutively expressed
Unlike many CYP enzymes, CYP2E1 is active even without substrate induction; ethanol, fasting, obesity, and diabetes all increase its expression further in the liver and, to a lesser extent, in the lungs, brain, and gut. The CYP2E1*4 allele (rs6413419) carries a single-letter DNA change that swaps the amino acid valine for isoleucine at position 179 of the protein — a substitution right within the enzyme's substrate-binding region.

The Mechanism

The G-to-A change at chromosome 10 position 133,532,171 (GRCh38 plus strand) converts a valine codon to an isoleucine codon²² valine codon to an isoleucine codon
Both are hydrophobic amino acids, but their side-chain geometry differs slightly, which can alter substrate positioning in the active site at protein position 179 (p.Val179Ile). The practical consequence depends on how sensitively the enzyme's catalytic efficiency responds to this geometric change. CYP2E1 metabolises its substrates via oxidative reactions that generate reactive intermediates: acetaminophen is converted to NAPQI (N-acetyl-p-benzoquinone imine), ethanol to acetaldehyde and then reactive oxygen species, and halogenated anesthetics to trifluoroacetylated liver-protein adducts that can trigger an immune reaction causing halothane hepatitis³³ halothane hepatitis
A rare, severe immune-mediated liver injury occurring after halothane or other halogenated anesthetic exposure; incidence ~1 in 10,000 after halothane, lower with newer agents. Whether the Val179Ile substitution increases, decreases, or leaves unchanged the rate of these reactions remains incompletely characterised; functional studies on specific CYP2E1 coding-region variants are limited, and a 2009 review found that coding-region missense alleles "did not consistently affect enzyme function" across published studies.

The Evidence

Direct in-vitro or clinical data on CYP2E1*4 enzyme kinetics is sparse. What is established is the general pharmacogenomics landscape: CYP2E1 is the principal enzyme responsible for oxidative halothane metabolism in human liver microsomes⁴⁴ CYP2E1 is the principal enzyme responsible for oxidative halothane metabolism in human liver microsomes
Spracklin et al. J Pharmacol Exp Ther 1997, producing the reactive trifluoroacetyl intermediates that cause immune-mediated liver injury. Higher CYP2E1 activity amplifies this risk; lower activity would theoretically reduce it. For acetaminophen, CYP2E1 is the dominant generator of the hepatotoxic metabolite NAPQI⁵⁵ CYP2E1 is the dominant generator of the hepatotoxic metabolite NAPQI
Harjumäki et al. Int J Mol Sci 2021; CYP2E1 knockout mice show dramatically reduced acetaminophen hepatotoxicity — making CYP2E1 activity directly relevant to safe dosing thresholds. For isoniazid (the first-line tuberculosis drug), rapid CYP2E1 metabolizers accumulate more toxic isoniazid intermediates⁶⁶ rapid CYP2E1 metabolizers accumulate more toxic isoniazid intermediates
Perwitasari et al. Drug Metab Rev 2015, explaining why CYP2E1 status predicts hepatotoxicity risk during TB treatment.

Population data from ALFA (dbSNP) confirm that rs6413419 is strikingly population-stratified: the A allele reaches ~20% allele frequency in African-ancestry populations but is extremely rare in East Asians (<0.01%) and uncommon in Europeans (~2.4%). Multiple studies in South Indian and Spanish cohorts found the variant to be monomorphic or absent, consistent with regional rarity. The functional significance of *4 specifically in these substrate pathways has not been resolved in a large, well-powered clinical or biochemical study — placing this variant at the emerging evidence tier.

Practical Actions

For the GG genotype (non-carriers), standard dosing guidelines apply for all CYP2E1 substrates. For AG heterozygotes and AA homozygotes, the key actionable areas are acetaminophen dosing caution, anesthetic choice disclosure, and awareness of isoniazid hepatotoxicity risk. Because the *4 allele's net effect direction (increased vs. decreased activity) is not yet definitively established by functional studies, clinical management focuses on disclosing CYP2E1 variant status to prescribers and hepatology teams rather than hard dose adjustments.

Interactions

CYP2E1*4 (rs6413419) shares the same gene with two other catalogued GeneOps variants: rs2070672 (a promoter *1C variant affecting transcription) and rs2515641 (a synonymous exon-8 variant that reduces mRNA and protein expression). Individuals carrying multiple CYP2E1 variant alleles — particularly rs2515641 on one chromosome and *4 on the other — would be compound heterozygotes for reduced CYP2E1 activity, potentially amplifying the effect on acetaminophen and isoniazid safety thresholds. No dedicated compound-phenotype study of *4 with these other variants has been published to date.