TM6SF2 Genotype (p.Glu167Lys)

If your cholesterol and triglycerides look good but you still worry about your liver, this gene variant may explain why those two stories can drift apart. People who carry the T (Lys167) allele of TM6SF2 tend to have lower LDL cholesterol and triglycerides while quietly accumulating more fat inside the liver.

Knowing your TM6SF2 status reframes how you read the rest of your labs. A favorable lipid panel does not automatically mean low liver risk, and a borderline ALT may carry more weight in someone who carries this variant.

What This Gene Actually Does

TM6SF2 (transmembrane 6 superfamily member 2) is a protein made mostly in the liver and small intestine. It sits inside the cell's packaging machinery (the endoplasmic reticulum and ER-Golgi compartment) and helps load fat onto VLDL (very low density lipoprotein), the liver's main fat-carrying particle that ships triglycerides into the bloodstream.

The p.Glu167Lys variant (also called E167K or rs58542926) swaps one amino acid in the protein. This single change makes the protein misfold and break down faster, leaving carriers with reduced TM6SF2 function. The result: fewer large, triglyceride-rich VLDL particles leave the liver. In one human study of homozygous carriers, production of VLDL1-triglyceride was 35% lower than in non-carriers. Less fat shipped out means more fat parked inside liver cells.

Fatty Liver and MASLD Risk

The T allele modestly raises the odds of fatty liver disease. A 2022 meta-analysis of 123,800 individuals across 44 studies found adults carrying the T allele had about 1.6-fold the odds of NAFLD (odds ratio 1.62, 95% confidence interval 1.40 to 1.86) compared with non-carriers, with a larger effect in children (odds ratio 2.87). In a Finnish study using MR spectroscopy, carriers had substantially more liver fat than non-carriers.

This effect shows up early. In a study of 1,010 obese children, the 167K allele was strongly tied to ultrasound-detected steatosis and higher ALT levels. In Chinese children, the variant was an independent risk factor for MASLD (metabolic dysfunction-associated steatotic liver disease).

Fibrosis, NASH, and Cirrhosis

Beyond simple fat accumulation, the variant pushes liver disease toward worse forms. A biopsy-based study of 1,201 adults with suspected NASH linked the T allele to advanced fibrosis and cirrhosis, independent of age, body weight, diabetes, and the better-known PNPLA3 variant. In a large general-population analysis combining TM6SF2 with PNPLA3 and HSD17B13, people in the highest genetic risk group had a 12-fold higher risk of cirrhosis and a 29-fold higher risk of liver cancer than those in the lowest.

Carriers with NAFLD are also more likely to have NASH (nonalcoholic steatohepatitis), the inflammatory form of fatty liver that drives scarring. The size of the effect varies across studies, but the pattern is consistent: the same gene change that traps fat in the liver also nudges the disease toward inflammation and scarring.

Viral Hepatitis and Coinfection

In chronic hepatitis C, a meta-analysis found the T allele raises the risk of advanced steatosis, fibrosis, and cirrhosis while lowering circulating triglycerides and non-HDL cholesterol. In adults coinfected with HIV and hepatitis C, carrying the variant independently predicted severe fibrosis. Background liver disease and the variant compound each other.

Lower Cholesterol and Lower Heart Attack Risk

Here is where the story turns. The same biology that traps fat in the liver also keeps it out of the bloodstream. Across population studies and meta-analyses, T allele carriers consistently show lower total cholesterol, lower LDL cholesterol, and lower triglycerides. A study of over 10,000 adults found this variant influences total cholesterol levels at genome-wide significance and tracks with reduced risk of myocardial infarction (heart attack). Other analyses have found protection against coronary artery disease.

Resolving the Apparent Contradiction

It looks paradoxical: how can one gene change be bad for your liver but good for your heart? It is not a contradiction once you see what the protein does. TM6SF2 controls a single transport step, the export of fat from liver into blood. Throttle that step and you change two things at once. You raise liver fat (worse for the liver) and you lower the circulating fat-carrying particles that drive heart disease (better for the arteries). The variant is not a global good or bad signal. It is a phenotype indicator that splits liver risk and cardiovascular risk in opposite directions.

How This Result Differs From Standard Labs

A standard lipid panel will likely look reassuring in a T allele carrier. That is precisely the problem. A study of obese children showed carriers had the lowest LDL cholesterol in the cohort while having the highest rates of steatosis and elevated ALT. If you only watch cholesterol, you can miss the liver entirely. This is a one-time test that does not change over your lifetime, but its result reshapes how you interpret every future liver and lipid panel.

Tracking Your Trend Around This Result

Your genotype itself never changes. What does change is what you do with it. A T allele carrier should treat ALT, AST, GGT, and imaging-based liver fat (MR spectroscopy or controlled attenuation parameter on FibroScan) as the trend lines that matter. Get a baseline of those liver markers and a fibrosis estimate (such as FIB-4) as soon as you know your TM6SF2 result. Recheck in 3 to 6 months if you are making lifestyle changes, then at least annually. A single normal ALT is reassuring. A rising trend over two or three readings is a signal worth investigating before it becomes a diagnosis.

What an At-Risk Result Should Prompt You to Do

If you carry the T allele, the next step is not panic, it is patterning. Pair your genotype with FIB-4, ALT, AST, GGT, fasting insulin, and ideally an elastography-based measurement of liver stiffness and steatosis. PNPLA3 genotyping adds meaningfully, because the two variants behave additively. In a 637-patient MASLD study, adding PNPLA3 and TM6SF2 genotypes to FIB-4 raised the area under the curve for advanced fibrosis prediction by 0.058 (p=0.010). If your FIB-4 is intermediate or rising, or if your imaging shows steatosis, that is the point to involve a hepatologist. The combination of T allele plus rising liver enzymes plus imaging-confirmed steatosis is the pattern that warrants specialist input, even when your cholesterol numbers look fine.

When Genotype Results Can Be Misleading

• Direct-to-consumer reports: one analysis found about 40% of variants reported in raw consumer genetic data were false positives when checked by a clinical lab. Confirm an unexpected result with clinical-grade genotyping before acting.
• Single-variant tunnel vision: TM6SF2 explains only part of the picture. People with elevated liver fat and a wild-type TM6SF2 result still have ample reason to evaluate liver health through other markers.
• Misreading the lipid signal: lower LDL and triglycerides in a carrier are a consequence of trapped hepatic fat, not a sign of cardiovascular invincibility. Other heart disease risks (ApoB, Lp(a), blood pressure, glucose) still apply.
• Ethnic and cohort variability: effect sizes shift across populations, and homozygotes are rare. A single result is informative, but the strength of risk attribution comes from combining it with phenotypic markers.

Where This Fits in the Larger Picture

TM6SF2 p.Glu167Lys is a modifier, not a diagnosis. It does not seal your fate. It sharpens the questions you should be asking about your liver, often before any standard panel would have flagged a problem. Used alongside ApoB, fasting insulin, ALT, FIB-4, and PNPLA3, it tells you which surveillance pathway your biology actually fits.