PNPLA3 rs28927680: Understanding the S453I Variant
The PNPLA3 rs28927680 variant, also known as S453I, is a rare genetic change located within the PNPLA3 gene. Research has investigated this variant for its potential role in hepatic lipid remodeling and its association with the progression of non-alcoholic fatty liver disease.
What each genotype means
Typical hepatic lipid metabolism
This genotype represents the common, non-variant form of the PNPLA3 gene at this position. Research indicates this version of the enzyme functions normally in the regulation of liver fat, and it is not associated with the increased risk of fatty liver disease observed with the alternative variant.
This is the most common genotype across most global populations.
Potentially altered lipid processing
Carrying one copy of the T allele (S453I) may influence how your liver processes fats, though evidence for this specific variant is limited compared to other PNPLA3 markers. Some studies suggest this variant may be associated with lower hepatic fat content in specific populations, but its clinical significance remains an area of ongoing research.
This genotype is rare, occurring with a frequency below 0.01 in most populations.
Variant hepatic lipid profile
This genotype involves two copies of the S453I variant, which has been studied for its role in hepatic lipid remodeling. While some research associates this variant with lower liver fat levels in specific groups, the overall clinical impact is not fully established; please consult with a healthcare provider to discuss any concerns regarding liver health.
This is a very rare genotype, found in less than 1% of the population.
What is the rs28927680 Variant?
The rs28927680 variant is a single nucleotide polymorphism (SNP) located in the PNPLA3 gene, which encodes the protein adiponutrin. In genetic terms, this variant results in a non-synonymous amino acid substitution where serine is replaced by isoleucine at position 453 (S453I). While many SNPs are common throughout the human population, rs28927680 is classified as a rare variant. It sits within the coding region of the gene, meaning it has the potential to alter the structure or function of the resulting protein. Scientists study such variants to understand how specific changes in our genetic code might influence biological processes, particularly those related to how the liver processes and stores fats.
The Role of the PNPLA3 Gene
The PNPLA3 gene provides instructions for making a protein that is primarily expressed in the liver and adipose tissue. This protein is known to play a significant role in lipid metabolism, specifically in the synthesis, hydrolysis, and storage of triglycerides. Because the liver is the central hub for fat metabolism, the function of PNPLA3 is critical for maintaining healthy lipid levels. When the PNPLA3 protein functions normally, it helps regulate the balance of fat within liver cells. Research into this gene has gained significant attention because variations in its sequence have been linked to differences in how individuals accumulate fat in the liver, which is a key factor in the study of non-alcoholic fatty liver disease (NAFLD).
Research Associations and Evidence
Scientific research has identified that certain variants in PNPLA3 can influence hepatic fat content. While the well-known rs738409 variant is widely recognized for its strong association with liver fat accumulation, rs28927680 has also been identified in studies exploring the genetic landscape of liver health. Some research suggests that this specific variant may be associated with lower hepatic fat content, contrasting with other variants in the same gene that are linked to increased risk. However, the evidence strength for rs28927680 remains limited. Current findings are largely based on observational studies, and the exact biochemical mechanism by which this specific substitution affects triglyceride hydrolase capacity is still being explored by the scientific community.
Population Frequency
The rs28927680 variant is considered rare, with a population frequency typically reported below 0.01 across most major ancestral groups. Because it is not a common variant, it is not frequently encountered in large-scale population screenings. Its rarity means that there is less data available compared to more common genetic markers, which contributes to the current limited understanding of its clinical significance. Researchers often rely on specialized cohorts to study such rare variants, as the small number of carriers makes it challenging to draw broad conclusions about its impact on health across diverse populations.
Interpreting Genetic Information
It is important to understand that genetic variants like rs28927680 are only one piece of a very complex puzzle regarding liver health. Many factors, including diet, physical activity, alcohol consumption, and other genetic markers, contribute to the development of conditions like fatty liver disease. Having a specific genotype does not mean an individual will develop a particular health condition, nor does it guarantee protection. If you have questions about your liver health or the results of a genetic test, you should discuss them with a qualified healthcare provider or a genetic counselor. They can help you interpret these findings in the context of your overall health history and provide appropriate guidance.
How common is this variant?
The rs28927680 variant is a rare genetic marker with a frequency below 0.01 in most global populations.
Frequently asked questions
What is the PNPLA3 gene?
The PNPLA3 gene encodes a protein called adiponutrin that is involved in the metabolism of fats in the liver. It plays a key role in how liver cells store and break down triglycerides.
Is rs28927680 the same as the common fatty liver variant?
No, rs28927680 is a different variant than the well-studied rs738409. While both are in the PNPLA3 gene, they have different effects and frequencies.
Should I be worried if I have this variant?
Genetic variants are only one factor in health. You should consult with a doctor to discuss your overall health, lifestyle, and any concerns about liver function.
Can I change my genetics?
You cannot change your genetic code. However, lifestyle choices such as maintaining a healthy diet and regular exercise are known to significantly influence liver health regardless of your genotype.
Sources & further reading
Educational information only, last refreshed 9/21/2026. Not medical advice — these associations describe population statistics, not individual predictions.
Curious what your genotype is for rs28927680?
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 PNPLA3
The p.Ile148Met variant in PNPLA3 is a major genetic determinant of hepatic fat content and NAFLD risk.
Intronic regulatory variant in linkage disequilibrium with I148M associated with hepatic fat fraction and ALT levels.
This variant is in high linkage disequilibrium with the I148M (rs738409) variant, which is a major genetic determinant of hepatic fat content and susceptibility to NAFLD.
An intronic variation in linkage disequilibrium with the major PNPLA3 non-alcoholic fatty liver disease (NAFLD) locus that contributes to individual liver fat accumulation and fibrosis predisposition.
The PNPLA3 I148M variant is a major genetic risk factor for non-alcoholic fatty liver disease (NAFLD) and progression to cirrhosis.
This variant is associated with increased risk of non-alcoholic fatty liver disease and liver fat accumulation.