rs4986893
badMag 7.5This is a stop gained variant in the CYP2C19 gene.
Key Literature Trait Associations
Clopidogrel Response
CYP2C19*3 introduces a premature stop codon, completely abolishing enzyme activity. Most prevalent in East Asian populations (~5-8%). Carriers are poor metabolizers of clopidogrel, proton pump inhibitors (omeprazole), and several antidepressants.
Warfarin dose requirement
The rs4986893 A allele (CYP2C19*3) reduces CYP2C19-mediated warfarin metabolism, resulting in a ~10% lower warfarin maintenance dose requirement in carriers compared to GG homozygotes. A 2022 systematic review and meta-analysis of 1,393 patients across nine studies confirmed this pharmacokinetic effect. While clinically meaningful, the overall contribution of CYP2C19 to warfarin dosing is modest compared to CYP2C9 and VKORC1, and the effect of *3 alone is primarily relevant in East Asian populations where the allele is more common.
Major depressive disorder
A candidate-gene study in Han Chinese found the rs4986893 A allele present at higher frequency in MDD patients (MAF 0.055) vs. controls (MAF 0.026), yielding OR 2.178. Intermediate and poor CYP2C19 metabolizer status (driven by *2 and *3 alleles combined) was also associated with MDD risk (OR 1.547). This association is biologically plausible given CYP2C19's role in metabolizing antidepressants, but the evidence rests on a single small study (n=903) and requires independent replication in larger cohorts before clinical weight can be assigned.
▶ClinVar annotation
MEPHENYTOIN, POOR METABOLISM OF; PROGUANIL, POOR METABOLISM OF; not provided; CYP2C19: no function; Acute coronary syndrome; Clopidogrel response
View on ClinVar →▶Research that mentions this SNP (5)
▶Interindividual Variability in the Hepatic Expression of the Human Breast Cancer Resistance Protein (BCRP/ABCG2): Effect of Age, Sex, and GenotypeAssociationN=1,000Bhagwat Prasad et al.(2013)· Journal of Pharmaceutical Sciences
Case-control study of 1,000 Han Chinese individuals (450 epilepsy cases, 550 controls) examining associations between STX1B polymorphisms and epilepsy treatment response. The rs140820592 variant showed significant association with reduced epilepsy risk (OR=0.542, p=0.004) and drug-resistant epilepsy risk (OR=0.260, p=0.004), with eQTL analysis confirming rs140820592 regulates STX1B expression in brain tissues.
▶Variants in ABCB1 , TGFB1 , and XRCC1 genes and susceptibility to viral hepatitis A infection in Mexican AmericansAssociationN=6,779Lyna Zhang et al.(2012)· Hepatology
Candidate gene association study of 67 genetic variants in 27 inflammation and DNA repair genes with hepatitis A virus (HAV) infection susceptibility in 6,779 NHANES III participants (2,619 non-Hispanic whites, 2,095 non-Hispanic blacks, 2,065 Mexican Americans). Among Mexican Americans, ABCB1 rs1045642 T allele was associated with lower HAV seropositivity risk (OR=0.79, p<0.001), while TGFB1 rs1800469 and XRCC1 rs1799782 T alleles were associated with increased risk (OR=1.38 and 1.57, respectively). CAT rs769214 and CYP2E1 rs2031920 showed marginal associations with decreased and increased HAV risk, respectively.
▶Influence of neurexin 1 (NRXN1) polymorphisms in clozapine responseReviewRenan P. Souza et al.(2010)· Human Psychopharmacology: Clinical and Experimental
This systematic review of 98 studies examined biological predictors of clozapine response in treatment-resistant schizophrenia patients. Of 379 different gene variants investigated across 70 genetic studies, only three variants (DRD3 Ser9Gly rs6280, HTR2A His452Tyr, and GNB3 C825T) achieved independent replication. Non-genetic predictors included higher prefrontal cortical volumes and lower HVA:5-HIAA ratio in cerebrospinal fluid.
▶Association of Cytochrome P450 2C19 Genotype With the Antiplatelet Effect and Clinical Efficacy of Clopidogrel TherapyAssociationN=656Shuldiner AR et al.(2009)· JAMA
This genome-wide association study identified the CYP2C19*2 loss-of-function variant (rs4244285) as a major determinant of clopidogrel response in 429 Amish individuals. The variant was associated with diminished platelet aggregation response to ADP stimulation (P=4.3×10⁻¹¹) and accounted for 12% of variation in clopidogrel response. In an independent cohort of 227 patients undergoing percutaneous coronary intervention, carriers of CYP2C19*2 had higher cardiovascular event rates (20.9% vs 10.0%, HR=2.42, P=.02).
▶Lack of association of GPX1 and MnSOD genes with symptom severity and response to clozapine treatment in schizophrenia subjectsReviewRenan P. Souza et al.(2009)· Human Psychopharmacology: Clinical and Experimental
A systematic review of 98 studies investigating biological predictors of clozapine response in treatment-resistant schizophrenia. Of 70 genetic studies examining 379 variants, only three genetic variants have independently replicated findings: DRD3 Ser9Gly (rs6280), HTR2A His452Tyr, and GNB3 C825T (rs5442/rs5443). Non-genetic predictors include higher prefrontal cortical structural integrity and activity, and lower HVA:5-HIAA ratio in cerebrospinal fluid.
Gene information from NCBI Gene. Variant classifications from ClinVar.
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