SLC22A1 rs35573682: Understanding the OCT1 Met420del Variant
The rs35573682 variant (historically cross-referenced as rs72552763) is an in-frame deletion in the SLC22A1 gene resulting in the OCT1 Met420del protein change. This alteration causes reduced cellular transport of organic cations, notably diminishing hepatic uptake of the first-line diabetes drug metformin. Research associates this variant with variability in glycemic response and gastrointestinal tolerance, though clinical evidence across diverse cohorts remains limited and nuanced.
What each genotype means
Normal transporter function
This genotype represents the most common form of the SLC22A1 gene, which encodes the OCT1 protein responsible for cellular metformin uptake. Individuals with this genotype typically exhibit standard transporter activity, though clinical response to metformin can still be influenced by other genetic and environmental factors. Please discuss your medication management and glycemic control with your healthcare provider.
This is the most prevalent genotype in most global populations, though exact frequencies vary significantly by ancestry.
Reduced transporter function
This genotype includes one copy of the variant associated with the Met420del mutation, which may lead to reduced cellular uptake of metformin. Research suggests that carriers of this variant might experience altered glycemic responses to metformin therapy compared to those without the variant. You should consult your clinician or pharmacist regarding your specific treatment plan and monitoring.
Carried by a significant portion of European and American populations, with the minor allele frequency for this variant typically ranging between 15% and 22%.
Decreased transporter function
This genotype involves two copies of the variant associated with the Met420del mutation, which is linked to decreased function of the OCT1 transporter. Studies indicate this may result in reduced metformin uptake into cells, potentially impacting how well the medication lowers blood glucose levels. It is important to discuss your medication dosing and therapeutic goals with your healthcare provider.
This homozygous genotype is less common than the heterozygous form, occurring in a smaller percentage of the population depending on ancestral background.
What Is rs35573682 and Where Is It Located?
The genetic identifier rs35573682 refers to an in-frame trinucleotide deletion in the SLC22A1 gene located on chromosome 6. In genetic literature and pharmacogenomics databases, it is frequently described as the OCT1 Met420del variant (often cataloged alongside rs72552763). This deletion leads to the loss of a single methionine amino acid residue at position 420 of the encoded transporter protein without disrupting the remaining translational reading frame. Unlike premature stop mutations that truncate proteins entirely, Met420del produces a full-length transporter that integrates into the cellular membrane but exhibits impaired conformational activity or reduced substrate affinity. Because it is an in-frame deletion of coding DNA, direct testing often reports alleles as either the reference insertion (Ins or non-deleted allele) or the deletion allele (Del). While it was once evaluated primarily as a candidate polymorphism in targeted assays, modern genomic datasets such as gnomAD catalog it as one of the most widespread functional alterations in human organic cation transport pathways.
The Biological Function of SLC22A1 and OCT1
The SLC22A1 gene provides instructions for producing Organic Cation Transporter 1 (OCT1), a multi-pass transmembrane protein situated predominantly in the sinusoidal membrane of human hepatocytes (liver cells) and along intestinal epithelial cells. As a solute carrier, OCT1 mediates the facilitated influx of endobiotics and xenobiotics from the blood circulation into liver tissue. Its primary pharmacological substrate is metformin, the standard foundational oral medication prescribed worldwide for type 2 diabetes management. To suppress gluconeogenesis and activate adenosine monophosphate-activated protein kinase (AMPK), metformin requires carrier-mediated transport across hepatocyte membranes because it carries a permanent positive charge at physiological pH. When OCT1 function is disrupted—as seen in carriers of the Met420del variant—cellular clearance and uptake of organic cations in hepatic tissue decreases significantly. This alters the drug's localized biodistribution, potentially shifting more unabsorbed medication into systemic circulation or leaving higher concentrations localized in the gastrointestinal lumen.
Current Research, Glycemic Response, and Gastrointestinal Tolerance
Clinical pharmacology studies have repeatedly investigated whether reduced-function SLC22A1 alleles modify therapeutic outcomes in patients taking metformin. Several trials and systematic reviews indicate that individuals carrying the Met420del variant exhibit attenuated HbA1c reductions during initial metformin monotherapy, presumably because lower hepatic uptake restricts activation of glucose-lowering cascades within liver cells. Furthermore, altered intestinal transport has led investigators to evaluate metformin-induced gastrointestinal side effects, such as nausea, abdominal cramping, and diarrhea. Some clinical studies report that homozygous or heterozygous carriers of reduced-function alleles face an increased likelihood of gastrointestinal intolerance due to localized mucosal accumulation. However, overall evidence strength remains categorized as limited by pharmacogenomic curators: across multiple large population cohorts and meta-analyses, findings have occasionally conflicted, with some cohorts showing negligible differences in long-term glycemic control. These discrepancies highlight that metformin efficacy is polygenic and heavily modulated by renal transporters, diet, renal function, and body mass.
Population Frequency and Global Distribution
Unlike many loss-of-function variants that are exceedingly rare, the Met420del polymorphism is widely distributed across global human populations. Global genomic surveys indicate that it is the most ubiquitous loss-of-function OCT1 allele on earth. Minor allele frequencies range between 15% and 22% in European and Admixed American populations, meaning that a significant proportion of individuals in these groups carry at least one copy of the deletion. Conversely, the deletion allele is observed at substantially lower frequencies in other ancestral lineages, falling below 5% to 7% in individuals of African ancestry and appearing at frequencies below 1% to 2% across East Asian populations. Because the prevalence of this variant varies markedly depending on geographic and genetic heritage, pharmacogenomic testing yields substantially different predictive values across multi-ethnic populations. Researchers emphasize that population-specific baseline allele rates must be factored into clinical association studies to prevent confounding.
Clinical Interpretation: What This Information Means for You
Understanding your SLC22A1 genotype can provide valuable insight into how your liver cells handle organic cations, but it is not a direct medical diagnosis or a prescription guide. The Clinical Pharmacogenetics Implementation Consortium (CPIC) and international regulatory agencies do not currently mandate routine OCT1 testing before initiating metformin, primarily because therapy adjustments are guided by clinical monitoring of blood sugar, HbA1c levels, and patient tolerance. If your genetic test indicates that you carry one or two copies of the rs35573682 deletion, you must never alter, discontinue, or adjust your medication dosing independently. Instead, discuss any ongoing medication side effects, gastrointestinal distress, or sub-optimal glucose control with your prescribing physician or pharmacist. Clinicians evaluate a wide array of factors—including liver and kidney function tests, lifestyle modifications, and concomitant therapies—to safely tailor your diabetes management plan.
How common is this variant?
The rs35573682 deletion allele is common in European and American populations, with minor allele frequencies typically between 15% and 22%. In contrast, it is less common in individuals of African ancestry (approximately 5%) and rare in East Asian populations (<2%).
Frequently asked questions
Does carrying rs35573682 mean metformin will not work for me?
No, carrying the rs35573682 deletion does not mean metformin will fail to work. While studies show that reduced OCT1 activity can attenuate hepatic uptake and slightly modify average HbA1c lowering, many carriers still achieve adequate blood sugar control. You should never stop or change your medication without consulting your healthcare provider.
Can this genetic variant cause stomach upset or diarrhea with metformin?
Some clinical studies have observed an increased rate of gastrointestinal side effects—such as nausea, abdominal discomfort, and diarrhea—in carriers of OCT1 loss-of-function variants like Met420del. This is hypothesized to occur because reduced transporter uptake leaves higher concentrations of the drug in the digestive tract. However, clinical findings remain mixed, and not all carriers experience adverse effects.
Why hasn't my doctor ordered genetic testing for OCT1 before prescribing metformin?
Standard clinical guidelines currently do not recommend routine OCT1 testing prior to initiating metformin therapy because evidence regarding clinical utility is categorized as limited. Instead, physicians routinely monitor drug efficacy and safety through direct HbA1c measurements, kidney function tests, and clinical evaluation of any gastrointestinal symptoms.
What should I do if my genetic test shows I carry the Del allele?
If your test shows one or two copies of the Met420del allele, you should share the report with your doctor or pharmacist. They can assess your overall glycemic response, review any digestive symptoms, and ensure your treatment regimen is optimized safely without making speculative changes to your dosage.
Sources & further reading
Educational information only, last refreshed 9/7/2026. Not medical advice — these associations describe population statistics, not individual predictions.
Curious what your genotype is for rs35573682?
Upload a raw DNA file from 23andMe, AncestryDNA, MyHeritage, or FamilyTreeDNA and see this variant — plus thousands more — interpreted in your full report.
Get my report — $29Related variants in SLC22A1
Functional non-synonymous variant (M420del) in the organic cation transporter OCT1, significantly impacting the hepatic uptake of various drugs including metformin.
An intronic variant in the organic cation transporter gene associated with altered metformin side-effect profiles.
A variant associated with the occurrence of gastrointestinal side effects in metformin users.
Variant in SLC22A1 (OCT1) associated with altered metformin transport and glycemic response.
Also known as OCT1 p.Met420del, this loss-of-function deletion diminishes hepatic uptake and glycemic response to metformin in patients with type 2 diabetes.
A missense variant in OCT1 that impairs organic cation cellular uptake, altering clinical responsiveness and gastrointestinal tolerance to metformin.