What you carry at this position in your DNA and what research says about it.
Fatty Liver Risk: 10/10 evidence, 41 publications.
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Sample genotype (not yours): C/C
Typical Fatty Liver Risk
Inheriting two copies of the C allele is associated with standard liver fat clearance and a lower risk of liver disease. A minor trade-off includes a slightly higher susceptibility to gout and cardiovascular issues.
What this genotype means: Standard liver fat clearance; Lower risk of cirrhosis; Slightly higher gout susceptibility.
Sample genotype (not yours): C/T
Increased Fatty Liver Risk
Carrying one copy of the T allele is linked to moderate fat accumulation in the liver and elevated liver enzymes. This increases the long-term risk of progressive liver conditions.
What this genotype means: Moderate liver fat accumulation; Elevated ALT and AST enzymes; Slightly increased risk of cirrhosis.
Sample genotype (not yours): T/T
Highly Increased Fatty Liver Risk
Inheriting two copies of the T allele significantly increases the risk of liver fat buildup, cirrhosis, and elevated liver enzymes. Proactive metabolic management is highly beneficial.
What this genotype means: Significant liver fat accumulation; Highly elevated liver enzymes; Increased risk of liver cirrhosis.
Gene function and biological role
Gene Function: The PNPLA3 gene encodes patatin-like phospholipase domain-containing protein 3, also known as adiponutrin, which is primarily active in liver and fat cells. This protein plays a critical role in regulating lipid metabolism by helping break down triglycerides and other fats. When the gene is functioning normally, it balances fat storage and mobilization in hepatocytes. However, specific variations in this gene can lead to fat accumulation in the liver, triggering inflammation and cellular damage. Over time, this chronic fat buildup can progress to more severe liver conditions, including fibrosis, cirrhosis, and potentially liver cancer.
Variant Impact: The rs738408 variant is a synonymous single nucleotide change located in the PNPLA3 gene. Although it does not alter the amino acid sequence of the protein directly, it is in extremely tight linkage disequilibrium with the well-known missense variant rs738409. Because these two variants are almost always inherited together, rs738408 serves as a highly reliable genetic proxy for liver fat accumulation and related metabolic traits. The T allele of this variant is consistently associated with elevated liver enzymes and an increased risk of progressive liver diseases. Conversely, the C allele is linked to a slightly higher risk of cardiovascular issues and gout, reflecting a complex metabolic trade-off.
Key Insight: This synonymous variant acts as a genetic mirror for one of the most influential liver-health genes in the human genome, showing how silent mutations can track major disease risks due to genetic linkage.
Location: PNPLA3. Chromosome 22 · 22q13.31 · 43.9 Mb
Estimated prevalence by population
Global 60.3%; European 59.9%; African 74.1%; East Asian 37.6%; South Asian 58.2%; Americas 33.3%; Ashkenazi 62.2%; Finnish 60.9%; Middle Eastern 56.5%; Amish 52.9%.
Estimated CC genotype frequency.
Global 33.8%; European 35.0%; African 24.0%; East Asian 47.4%; South Asian 36.2%; Americas 48.8%; Ashkenazi 33.3%; Finnish 34.3%; Middle Eastern 37.3%; Amish 39.6%.
Estimated CT genotype frequency.
Global 5.9%; European 5.1%; African 1.9%; East Asian 14.9%; South Asian 5.6%; Americas 17.9%; Ashkenazi 4.5%; Finnish 4.8%; Middle Eastern 6.2%; Amish 7.4%.
Estimated TT genotype frequency.
Showing effects for C/C genotype
Organ Systems
Liver Function & Disease
Fatty Liver Disease. Evidence: 9/10. Source: PMID 35047847. Typical Risk.
Liver Cirrhosis. Evidence: 9/10. Source: PMID 31815349. Typical Risk.
ALT Liver Enzyme. Evidence: 10/10. Source: PMID 28090653. Typical Levels.
Cancer & Oncology
Gastrointestinal Cancers
Liver Cancer. Evidence: 10/10. Source: PMID 37340002. Typical Risk.
Cardiovascular & Metabolic
Heart Disease
Coronary Artery Disease. Evidence: 7/10. Source: PMID 35915156. Slightly Increased.
Gout & Uric Acid
Gout. Evidence: 8/10. Source: PMID 39024449. Slightly Increased.
Showing effects for C/T genotype
Fatty Liver Disease. Evidence: 9/10. Source: PMID 35047847. Increased Risk.
Liver Cirrhosis. Evidence: 9/10. Source: PMID 31815349. Increased Risk.
ALT Liver Enzyme. Evidence: 10/10. Source: PMID 28090653. Elevated Levels.
Liver Cancer. Evidence: 10/10. Source: PMID 37340002. Increased Risk.
Coronary Artery Disease. Evidence: 7/10. Source: PMID 35915156. Typical Risk.
Gout. Evidence: 8/10. Source: PMID 39024449. Typical Risk.
Showing effects for T/T genotype
Fatty Liver Disease. Evidence: 9/10. Source: PMID 35047847. Highly Increased Risk.
Liver Cirrhosis. Evidence: 9/10. Source: PMID 31815349. Highly Increased Risk.
ALT Liver Enzyme. Evidence: 10/10. Source: PMID 28090653. Highly Elevated Levels.
Liver Cancer. Evidence: 10/10. Source: PMID 37340002. Highly Increased Risk.
Coronary Artery Disease. Evidence: 7/10. Source: PMID 35915156. Slightly Lower Risk.
Gout. Evidence: 8/10. Source: PMID 39024449. Slightly Lower Risk.
What this genotype means for the people who carry it
Sample genotype: CC (Homozygous)
Normal lipid processing in liver cells helps prevent the accumulation of unwanted fat deposits. This genotype is highly protective against non-alcoholic fatty liver disease, liver cirrhosis, and liver cancer compared to carrying the T allele. Liver enzyme levels, such as alanine aminotransferase (ALT), typically remain within standard ranges under normal dietary conditions. However, large-scale genetic studies indicate that the C allele is associated with a modest increase in uric acid levels and gout risk. There is also a small, documented increase in coronary artery disease risk linked to this genetic profile. Maintaining a balanced diet and regular exercise helps optimize both liver and cardiovascular health.
Standard liver fat clearance; Lower risk of cirrhosis; Slightly higher gout susceptibility.
Sample genotype: CT (Heterozygous)
Altered lipid metabolism in hepatocytes can lead to a gradual buildup of triglycerides. This heterozygous genotype is associated with an elevated risk of developing non-alcoholic fatty liver disease. Clinical studies frequently observe higher baseline levels of liver enzymes like ALT and AST, which serve as markers for liver stress. Over time, this chronic fat accumulation can increase the likelihood of liver fibrosis and cirrhosis. On the other hand, carrying one copy of the T allele provides a slight buffer against the elevated gout and cardiovascular risks associated with the C/C genotype. Minimizing alcohol intake and managing metabolic factors like body weight are highly effective ways to support liver function.
Moderate liver fat accumulation; Elevated ALT and AST enzymes; Slightly increased risk of cirrhosis.
Sample genotype: TT (Homozygous)
Impaired breakdown of triglycerides in liver cells leads to substantial fat retention and cellular stress. This genotype is strongly linked to non-alcoholic fatty liver disease and its progression to severe liver damage. Multiple genome-wide studies show a highly elevated risk of liver cirrhosis and liver cancer for individuals with this profile. Liver enzymes, particularly ALT and AST, are frequently elevated and serve as key clinical indicators of ongoing liver inflammation. Interestingly, this genetic makeup is associated with a lower risk of coronary artery disease and gout compared to the C/C genotype. Focusing on a low-sugar diet, avoiding alcohol, and maintaining metabolic health are critical strategies to protect liver tissue.
Significant liver fat accumulation; Highly elevated liver enzymes; Increased risk of liver cirrhosis.
Variants with shared genetic architecture
rs3747207 · PNPLA3 Gene · Chr 22 · Fatty Liver Risk
rs738409 · PNPLA3 Gene · Chr 22 · Liver Fat and Disease Risk
rs2896019 · PNPLA3 Gene · Chr 22 · Liver Disease Risk
Content updated August 2026.
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