TM6SF2 Genotype (p.Glu167Lys)

You can have low cholesterol, low triglycerides, and a heart disease risk score your doctor calls reassuring, and still carry a genetic variant that is quietly pushing fat into your liver. That is the strange dual nature of TM6SF2 (transmembrane 6 superfamily member 2) p.Glu167Lys, often written as E167K or rs58542926.

Knowing your status here matters because the variant behaves like a trade. It lowers the kind of blood lipids that drive heart attacks while raising the chance of fatty liver disease, inflammation, and scarring. A standard lipid panel cannot show you this trade. A single test for this variant can.

What This Variant Actually Does

TM6SF2 is a protein made mostly in the liver and small intestine. Its job is to help load fat onto the particles that carry triglycerides out of the liver and into your bloodstream (called VLDL, or very low density lipoproteins). Think of the liver as a packing station that ships fat to the rest of the body. TM6SF2 is part of the loading dock.

The p.Glu167Lys change is a single letter swap in your DNA. The result is a protein that is unstable, gets broken down faster, and works less well. In carriers, expression of the variant protein is substantially reduced compared with the normal version, though the exact fraction varies between studies and model systems. Less working TM6SF2 means less fat shipped out of the liver, more fat stuck inside it, and lower fat and cholesterol traveling through your blood.

You carry two copies of the TM6SF2 gene, one from each parent. Most people carry two unchanged (Glu/Glu) copies. Some are heterozygous (Glu/Lys), and a smaller number are homozygous (Lys/Lys) for the variant. The more Lys copies you carry, the stronger the effect.

The Heart Disease Side of the Trade

Carriers consistently show lower total cholesterol, lower LDL cholesterol, and lower triglycerides than non-carriers. In a kinetic study of 20 people (10 homozygous carriers and 10 controls), homozygous carriers produced about 35% less triglyceride packaged in their largest VLDL particles. That single mechanism, less of the most artery-damaging fat-carrying particles entering circulation, helps explain why carriers tend to have a lower risk of heart attack.

Population studies have linked the variant to lower coronary disease risk and protection from myocardial infarction. The signal is consistent across large cohorts. If you carry the variant and look at your standard lipids, the numbers may look quite good without you having done anything special.

The Liver Side of the Trade

The fat that does not leave the liver has to go somewhere, and it stays in the liver. Carriers have more liver fat, more chance of fatty liver disease (now called MASLD, metabolic dysfunction associated steatotic liver disease, formerly NAFLD), and more risk of progression to inflammation and scarring.

In one Finnish study, carriers had meaningfully more liver fat than non-carriers measured by MR spectroscopy. In a meta-analysis, the variant roughly doubled the risk of NAFLD (odds ratio about 2.1). In a study of obese children, carriers had higher liver enzymes (ALT) and more imaging-confirmed liver fat, despite lower cholesterol and triglycerides.

Reconciling the Paradox

It is tempting to ask, is this variant good or bad? The honest answer is that it is neither. It is a phenotype indicator. It shifts where fat sits in your body. The risk it raises (liver injury, scarring) is in a different organ from the risk it lowers (artery disease). A carrier with a textbook lipid panel can still have a liver quietly accumulating fat. A non-carrier with high cholesterol still has high cholesterol. Both stories can be true at the same time. The clinical job is to track the right outcomes for the genotype you actually have.

Fibrosis and Steatohepatitis Risk

Beyond just storing fat, the liver of a carrier is more likely to show inflammation and scarring. In a large biopsy cohort of NAFLD patients, the variant was independently linked to NASH and advanced fibrosis, even after accounting for age, BMI, diabetes, and the other major liver-fat variant in PNPLA3. In a separate biopsy-based study, carriers had more steatosis and were more likely to have NASH (the inflammatory form of fatty liver).

The size of the effect on fibrosis varies between studies. Some cohorts find a strong, independent fibrosis signal. Others find an effect on fat but only a marginal or non-significant effect on fibrosis once other factors are controlled. The most reliable interpretation is that the variant is one of several genetic nudges toward worse liver outcomes, and its effect adds to other risks rather than replacing them.

Hepatitis C and HIV Coinfection

If you have chronic viral hepatitis, this variant matters more, not less. A meta-analysis of hepatitis C patients found that carrying the variant raised the risk of advanced steatosis, fibrosis, and cirrhosis, while lowering triglycerides and non-HDL cholesterol. In a cohort of people coinfected with HIV and hepatitis C, the variant was an independent predictor of severe liver scarring.

Cirrhosis and Liver Cancer

Large general-population data combining the TM6SF2 variant with two other fatty liver variants (PNPLA3 and HSD17B13) into a single risk score showed dramatically higher risk for the worst liver outcomes: about a 12-fold higher risk of cirrhosis and a 29-fold higher risk of liver cancer in people in the top genetic risk group (score 5-6) compared with the lowest (score 0). TM6SF2 alone is a smaller signal than that combined score, but it contributes meaningfully when stacked with other fatty liver risk variants.

Children and Family Risk

The liver consequences show up early. In obese children, carrying the variant was strongly associated with ultrasound-detected liver fat and higher ALT. In Chinese children, the variant was an independent risk factor for MASLD. If one parent or sibling has the variant, biological children, siblings, and parents each have a meaningful chance of carrying it themselves.

A One-Time Test, A Lifetime of Use

This is genetic. Your TM6SF2 status was set the moment your parents' DNA combined and it will not change. You only need to test it once. There is no reason to repeat the genotype unless a different testing method is needed to confirm a borderline call.

The value of this result is not in retesting the gene. The value is in what you start watching closely for the rest of your life. No major hepatology society currently endorses a specific surveillance schedule for TM6SF2 carriers, so the following intervals are expert-opinion suggestions rather than guideline-endorsed protocols. If you carry the variant, the labs and imaging that may be reasonable to track over time are the liver-specific ones: ALT and AST every 6 to 12 months, fasting insulin and glucose to catch metabolic drift early, and liver imaging or non-invasive fibrosis scores (such as FIB-4, a calculation that combines age, ALT, AST, and platelets to estimate scarring) every 1 to 3 years depending on your overall risk. Standard lipid panels, while still useful, can be misleadingly reassuring on their own.

Decision Pathway: What To Do With Your Result

If you are a carrier, the question is not whether to act today on a single number. It is how to fold this lifetime piece of information into the rest of your monitoring. The actions to consider:

• Companion genotyping: ask about PNPLA3 (rs738409) and HSD17B13 testing, since combined genotypes give a much sharper picture of liver risk than TM6SF2 alone.
• Liver imaging: consider a baseline liver ultrasound or, if available, MR-based fat quantification, especially if you have any metabolic risk factors (overweight, prediabetes, type 2 diabetes).
• Non-invasive fibrosis scoring: ask your clinician to calculate FIB-4 from your routine labs. Combined with this genotype, it has been shown to refine who needs closer follow-up.
• Specialist referral: if liver enzymes are persistently elevated, if imaging suggests significant steatosis, or if a fibrosis score is intermediate or high, a hepatologist (a liver specialist) can decide whether elastography or biopsy is appropriate.
• Family conversation: biological relatives share part of your DNA. If you are a heterozygous carrier, each first-degree relative has roughly a one in two chance of carrying the same variant. If you are homozygous (two copies), every one of your biological children will inherit at least one copy. Letting relatives know lets them decide whether to test.

When Results Can Be Misleading

Genetic testing has its own confounders. Unlike a hormone or cholesterol level, the genotype is not affected by fasting, exercise, sleep, illness, or medications. But the result you see can still be misleading for these reasons:

• Variant panel coverage: this test specifically looks at the p.Glu167Lys position. A normal result here does not rule out other rare variants in the TM6SF2 gene, some of which have also been linked to liver fat and liver cancer in genome-first studies.
• Ancestry and allele frequency: the frequency of this variant differs by ancestry, and the absolute risk it carries can differ between populations. The same genotype call means slightly different things across ethnic groups.
• Direct-to-consumer false positives: consumer genetic platforms have been shown in some studies to report a substantial share of false positives in raw data (around 40% in one analysis). A 'positive' on a consumer-grade report for TM6SF2 should be confirmed by a clinical-grade lab before acting on it.
• Variants of uncertain significance: if the test reports a rare TM6SF2 variant that is not p.Glu167Lys, its meaning may not yet be established. A clinical geneticist or genetic counselor can help interpret it.

What This Test Cannot Do

Carrying the variant does not mean you will develop fatty liver disease, fibrosis, or cancer. Many carriers never do, especially those who remain lean and metabolically healthy. Not carrying it does not mean you are safe. Standard drivers of liver disease, obesity, type 2 diabetes, heavy alcohol use, hepatitis B and C, still dominate the picture for most people. This test refines risk. It does not replace the rest of the workup.