rs2642438 — MTARC1 p.Ala165Thr (A165T)

Protective missense variant that reduces MTARC1 protein stability, cutting hepatic fat accumulation and lowering risk of NAFLD, NASH, and liver-related death

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MTARC1 A165T — The Liver-Protective Variant That Turns Down Hepatic Fat Storage

Your liver is the body's central hub for fat metabolism, processing everything from dietary fats to the lipids your own cells produce. The MTARC1 gene11 MTARC1 gene
mitochondrial amidoxime reducing component 1, formerly known as MARC1 encodes an enzyme anchored in the outer mitochondrial membrane that plays a surprising role in regulating hepatic lipid accumulation. The rs2642438 variant — specifically the A allele encoding the p.Ala165Thr amino acid change — is one of the clearest examples of a common protective variant in liver disease genetics. About 9% of people of European descent carry two protective copies, and 42% carry one. The effect scales with allele dose: more A alleles, less liver fat, lower risk of disease progression.

The Mechanism

At position 165 in the MTARC1 protein, the common G allele encodes an alanine residue that is critical for protein stability. When the A allele substitutes threonine at this position, the protein becomes dramatically less stable. Laboratory studies show the half-life of MTARC1 drops from 11.5 hours to just 3.5 hours in liver cells22 Laboratory studies show the half-life of MTARC1 drops from 11.5 hours to just 3.5 hours in liver cells
measured by cycloheximide chase assays in HepG2 and Huh-7 hepatocyte lines. The destabilized protein is rapidly degraded by the proteasome, reducing total MTARC1 levels in the cell by approximately 50%.

This matters because MTARC1 normally promotes fat accumulation in hepatocytes. When MTARC1 is reduced, the beta-oxidation rate doubles in primary human hepatocytes33 the beta-oxidation rate doubles in primary human hepatocytes
measured by radiolabeled palmitate oxidation assays — meaning the liver burns more fat rather than storing it. Protective allele carriers also show elevated plasma 3-hydroxybutyrate44 3-hydroxybutyrate
the ketone body produced as a byproduct of fatty acid beta-oxidation, confirming this accelerated fat oxidation in living humans from the UK Biobank. Additional mechanisms include increased hepatic phosphatidylcholine levels (particularly polyunsaturated species) and suppression of ferroptosis, an iron-dependent cell death pathway implicated in NASH progression.

The Evidence

The evidence for rs2642438 is unusually strong for a common metabolic variant. The seminal genome-first study analyzed over 460,000 participants in the UK Biobank plus 15,000 in the Penn Medicine BioBank55 460,000 participants in the UK Biobank plus 15,000 in the Penn Medicine BioBank
with median 10-12 year follow-up and full mortality ascertainment. Each A allele reduced NAFLD risk by approximately 15%. Homozygous AA individuals showed a hazard ratio of 0.61 (95% CI: 0.46–0.81) for liver-related death — a 39% reduction. In people with diabetes (who face amplified liver disease risk), the protection was even greater: HR 0.44 [0.22–0.86].

The protective effect holds across ancestries. While the A allele is rarer in people of African ancestry (~7% vs ~29% in Europeans), African American carriers in the Penn Medicine BioBank showed the same distinctive lipid phenotype and protective direction of effect. The A allele is also rarer in East Asian populations (~8%), making this predominantly a European-frequency protective variant.

A Mendelian randomisation analysis using multi-trait colocalisation66 Mendelian randomisation analysis using multi-trait colocalisation
treating the genetic variant as a natural experiment to infer causality confirmed that MTARC1 expression is causally related to liver fat, liver enzymes, and plasma lipids — ruling out confounding as an explanation for the associations. A targeted MTARC1 knockdown using GalNAc-siRNA in a diet-induced NASH mouse model reduced liver triglycerides, total cholesterol, and fibrosis gene expression, validating MTARC1 inhibition as a therapeutic strategy.

Importantly, the protective lipid profile of A allele carriers — lower LDL, lower ApoB, lower total cholesterol, higher triglycerides — does not translate into cardiovascular harm. Cardiac MRI and carotid ultrasound in the UK Biobank found no structural cardiac differences, and cardiovascular mortality was not increased.

Practical Actions

For people carrying the protective A allele (either one or two copies): the biology is working in your favor for liver health. Your hepatocytes are naturally more efficient at burning fat rather than storing it, and your baseline risk of NAFLD and liver fibrosis is meaningfully lower than the population average. This advantage is most clinically relevant if you carry risk variants at other liver-disease loci such as PNPLA3 (rs738409) or TM6SF2 (rs58542926), where MTARC1's protection can partially offset the harm.

For people carrying two G alleles (the most common genotype): you have typical MTARC1 protein stability and no extra protection against hepatic fat accumulation. Diet quality, alcohol avoidance, and metabolic health management are the main levers available. Choline-rich foods (eggs, liver, fish) support phosphatidylcholine synthesis, which is specifically depleted in NAFLD and lower in GG individuals compared to A allele carriers. Dietary saturated fat restriction is particularly important, as GG individuals process hepatic fat less efficiently.

Interactions

The MTARC1 protective effect is strongest in the context of other liver disease risk factors. In UK Biobank participants who also carried the PNPLA3 rs738409 G allele (which increases NASH risk), MTARC1 AA homozygotes showed a hazard ratio of 0.43 [0.27–0.71] for liver-related mortality — indicating the two genes interact epistatically. The MTARC1 A allele partially offsets PNPLA3-driven fibrosis risk. A similar protective interaction has been documented with HSD17B13 (rs72613567), another protective liver variant; individuals carrying protective alleles at multiple loci have additive reductions in fibrosis risk.

Nutrient Interactions

fat (dietary) altered_metabolism
choline altered_metabolism

Genotype Interpretations

What each possible genotype means for this variant.

GG Standard Liver Protection Normal

Typical MTARC1 activity — no extra protection against liver fat accumulation

The G allele at rs2642438 encodes alanine at position 165, a residue critical for MTARC1 protein stability. With two G alleles, you produce normal levels of MTARC1 in your hepatocytes. This means your liver's beta-oxidation rate is not genetically boosted, and your hepatic phosphatidylcholine profile is typical. In the UK Biobank, GG individuals showed higher ALT and AST levels on average than A allele carriers, and higher rates of NAFLD diagnosis over 10-12 years of follow-up. The absolute risk remains modest for healthy individuals, but the GG genotype means you don't have the extra genetic buffer that A allele carriers possess.

AG Partial Liver Protection Beneficial

One protective copy — meaningfully lower liver fat risk than average

One copy of the A allele is enough to partially destabilize MTARC1 protein. In a large genome-first study of 460,000+ UK Biobank participants, AG heterozygotes showed adjusted odds ratios of 0.86 [0.79–0.94] for NAFLD compared to GG homozygotes, and a hazard ratio of 0.85 [0.74–0.98] for liver-related mortality. The effect is dose-dependent: one copy gives partial protection, two copies give greater protection. Your plasma lipid profile will also tend toward lower LDL, lower ApoB, and slightly higher triglycerides compared to GG individuals — a phenotype that carries no cardiovascular downside based on cardiac imaging data from the same biobank cohort. If you also carry PNPLA3 rs738409 G alleles, your MTARC1 A allele provides partial counterbalance to that risk.

AA Strong Liver Protection Beneficial

Two protective copies — substantially lower liver fat, NAFLD, and fibrosis risk

In the UK Biobank genome-first study, AA homozygotes showed an adjusted hazard ratio of 0.61 [0.46–0.81] for liver-related death — a 39% risk reduction compared to GG individuals over 10-12 years. In participants who also carried PNPLA3 risk alleles, your MTARC1 AA genotype showed even stronger protection, with HR 0.43 [0.27–0.71] — indicating the two genes interact to amplify the MTARC1 protective effect in high-risk contexts. Mechanistically, your hepatocytes have a doubled beta-oxidation rate compared to GG cells, measurable both in primary human hepatocyte experiments and through elevated plasma 3-hydroxybutyrate in UK Biobank data. Your liver also produces more polyunsaturated phosphatidylcholines, which support membrane integrity and protect against hepatic inflammation. The lipid phenotype (lower LDL, lower ApoB, slightly higher triglycerides) does not increase cardiovascular risk — cardiac MRI and carotid ultrasound in the UK Biobank found no structural cardiac differences in AA individuals.