TM6SF2 Genotype (p.Asn139Lys)

If your cholesterol panel looks reassuring but your liver is quietly accumulating fat, you may carry a gene variant that flips the usual cholesterol-and-liver relationship on its head. This single inherited change in the TM6SF2 (transmembrane 6 superfamily member 2) gene increases your odds of developing nonalcoholic fatty liver disease by about 60% in adults while lowering your blood cholesterol and triglycerides at the same time.

The test reads one position in TM6SF2, the gene that controls how your liver exports fat. Your result is set at birth and never changes, but learning it now can change how aggressively you monitor your liver and how you interpret a clean lipid panel.

Fatty Liver Disease Risk

Carrying the risk version of this TM6SF2 variant raises your chance of fatty liver, called NAFLD (nonalcoholic fatty liver disease) or MASLD (metabolic dysfunction-associated steatotic liver disease) in newer guidelines. A 44-study meta-analysis pooling more than 123,000 people found about 1.6 times higher odds of NAFLD in adults who carry the risk allele, and almost three times higher odds in children.

The underlying biology is straightforward. The risk version of TM6SF2 makes a less functional protein, which slows down the liver's ability to package fat into very low-density lipoprotein (VLDL), the main fat-carrying particle the liver releases into the blood. Fat that cannot be exported stays in the liver. That is why this variant raises liver fat while lowering blood cholesterol and triglycerides.

Advanced Fibrosis and Cirrhosis

The risk version of TM6SF2 does more than just promote fat storage. In people who already have fatty liver, it is linked to scarring (fibrosis) and cirrhosis. A 2022 meta-analysis found about 1.5 times higher odds of advanced fibrosis in carriers, independent of age, weight, diabetes, and another well-known liver gene variant called PNPLA3. A separate biopsy cohort study found higher odds of nonalcoholic steatohepatitis (NASH) and a similar fibrosis signal.

The variant also predicts what happens after liver disease becomes advanced. In a study of 938 people with advanced chronic liver disease, carriers had about a 44% higher rate of hepatic decompensation, liver transplant, or liver-related death over follow-up, regardless of how sick their liver looked at the start. Not every fibrosis study has found the same effect, with one multicenter biopsy study showing a link to fat but not scarring, and one Eastern European cohort finding no link to fibrosis or cirrhosis at all. The signal is strong but not universal.

Sources: Li et al. 2022 (meta-analysis of NAFLD and fibrosis); Balcar et al. 2023 (advanced chronic liver disease cohort).

Liver Cancer Risk

Liver cancer evidence is more context-dependent. In a genome-wide study of alcohol-related hepatocellular carcinoma, the TM6SF2 risk allele was associated with about 1.77 times higher odds of liver cancer. An Egyptian case-control study in chronic liver disease also found higher risk-allele frequencies in people with liver cancer. A separate cohort of people with compensated cirrhosis did not find a link between this variant and liver cancer specifically, so the cancer signal seems strongest in alcohol-related disease and people already on the fibrosis-to-cirrhosis path.

The Liver-Heart Tradeoff

This is the most counterintuitive part of the result. The same TM6SF2 risk allele that raises your fatty liver odds also lowers your blood cholesterol and triglycerides and, in some studies, lowers your cardiovascular risk. A meta-analysis of more than 101,000 people found carriers had lower total cholesterol, LDL, and triglycerides. A community cohort analysis of millions of records showed opposite effects: the variant raised liver event rates while lowering major cardiovascular event rates.

This is not a contradiction. TM6SF2 controls how the liver ships fat into the blood. A less functional version traps fat inside the liver, which is bad for the liver but means less cholesterol and triglyceride circulating in your arteries. Think of it as the same dial turned in opposite directions for two different problems. A reassuring lipid panel does not rule out hidden liver risk in this group.

When Results Can Be Misleading

• Variant panel coverage: this assay only detects the specific variant it is designed to read. A negative result rules out that variant but not other rare changes in the same gene that could also affect liver fat handling.
• Naming differences: this test reports the variant as p.Asn139Lys, while the great majority of published research uses the E167K name. These two notations describe different amino acid changes (asparagine-to-lysine versus glutamic-acid-to-lysine), which can happen when different reference transcripts of the same gene are used to annotate the underlying variant, but it can also indicate a genuinely different change. If your report uses an unfamiliar notation, confirm with the testing laboratory which specific genetic variant (such as the rs58542926 single-letter DNA change) is being measured before comparing to research articles.
• Ancestry-specific frequencies: the variant is more common in some ancestry groups than others, and the risk-allele frequency in your background influences how meaningful a single positive result is.
• Direct-to-consumer reports: a result from a consumer genetics service is not the same as a clinical-grade test. If a 23andMe-style report flagged TM6SF2, a confirmatory clinical assay is appropriate before acting on it.

Your One-Time Result

Unlike cholesterol or liver enzymes, your TM6SF2 genotype does not change. You only need to test it once. The value of this test is not in repeating it, but in integrating the result into your ongoing decisions for the rest of your life.

If you carry the risk allele, the actionable testing is on the downstream phenotype. You should track liver enzymes (ALT, AST, GGT) at least annually, get a fibrosis estimate such as a FIB-4 score (a calculator that combines age, ALT, AST, and platelet count) every year or two, and consider liver elastography (a painless ultrasound-based stiffness scan) every few years or sooner if other risk factors are present. These tests, not the TM6SF2 genotype itself, are what change over time.

What to Do With an Unexpected Result

A positive result is not a diagnosis. It is a permanent input into your risk picture. The decision pathway depends on what other findings you have alongside it.

• If your liver enzymes and FIB-4 are normal: focus on metabolic risk factors that interact with this variant, particularly visceral fat, insulin resistance, and alcohol intake. Repeat liver enzymes and FIB-4 annually instead of every few years.
• If you have elevated liver enzymes or a borderline FIB-4: add liver elastography or a similar imaging-based fibrosis assessment. The combination of a TM6SF2 risk allele plus a non-invasive fibrosis score modestly improves detection of advanced scarring, especially if you have type 2 diabetes.
• If you have type 2 diabetes or known fatty liver: consider involving a hepatologist for a baseline fibrosis assessment. People with both the variant and these conditions had substantially higher 10-year rates of liver-related events in one biopsy cohort.
• If you have a family history of cirrhosis, liver cancer, or unexplained liver disease: a genetic counselor can help interpret your result in the context of family pattern and consider whether other family members would benefit from testing.