What you carry at this position in your DNA and what research says about it.
Liver Fat and Disease Risk: 10/10 evidence, 113 publications.
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Sample genotype (not yours): C/C
Typical Liver Fat and Lower Disease Risk
This genotype is associated with typical levels of liver fat and a lower risk of developing fatty liver disease. It also provides relative protection against alcohol-related liver damage.
What this genotype means: Typical liver fat levels; Lower risk of fatty liver disease; Slightly higher risk of gout.
Sample genotype (not yours): C/G
Increased Liver Fat and Moderate Disease Risk
Carrying one copy of the G allele is linked to increased accumulation of fat in the liver. This moderately raises the risk of fatty liver disease and cirrhosis.
What this genotype means: Elevated liver fat accumulation; Moderately increased risk of fatty liver disease; Higher risk of chemotherapy-induced liver toxicity.
Sample genotype (not yours): G/G
Significantly Higher Liver Fat and Disease Risk
Carrying two copies of the G allele is linked to high liver fat accumulation. This significantly increases the risk of fatty liver disease, cirrhosis, and liver cancer.
What this genotype means: High liver fat accumulation; Significantly increased risk of fatty liver disease and cirrhosis; Higher risk of chemotherapy-induced liver toxicity.
Gene function and biological role
Gene Function: The PNPLA3 gene encodes patatin-like phospholipase domain-containing protein 3, also known as adiponutrin [1]. This protein is primarily active in liver cells and fat cells, where it plays a key role in lipid metabolism [1]. It possesses both lipase activity to break down triglycerides and acyltransferase activity to build lipids [2]. Under normal conditions, PNPLA3 helps regulate the balance between fat storage and fat breakdown in the liver [2]. When functional, it facilitates the mobilization and secretion of fats from liver cells, preventing excessive intracellular accumulation [3].
Variant Impact: The rs738409 variant is a missense mutation in the PNPLA3 gene that causes an isoleucine-to-methionine substitution at position 148 [4]. This amino acid change alters the protein's structure, causing it to accumulate on the surface of intracellular lipid droplets rather than being cleared [3]. This accumulation impairs the normal breakdown of triglycerides, leading to a loss of function in lipid mobilization [3] [5]. As a result, fats build up inside liver cells, significantly increasing the risk of hepatic steatosis and progressive liver damage [5].
Key Insight: This variant is the single strongest genetic risk factor discovered for metabolic dysfunction-associated steatotic liver disease. Surprisingly, carriers of the risk allele can accumulate significant liver fat and develop fibrosis even if they maintain a healthy body weight and normal metabolic markers.
Location: PNPLA3. Chromosome 22 · 22q13.31 · 43.9 Mb
Estimated prevalence by population
Global 60.3%; European 59.9%; African 74.0%; East Asian 37.6%; South Asian 58.2%; Americas 33.2%; Ashkenazi 62.2%; Finnish 60.8%; Middle Eastern 56.5%; Amish 53.0%.
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 CG 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 GG genotype frequency.
Showing effects for C/C genotype
Organ Systems
Liver Function & Disease
Fatty Liver Disease. Evidence: 10/10. Source: PMID 21423719. Typical Risk.
Liver Fat. Evidence: 10/10. Source: PMID 32247823. Typical.
Liver Cirrhosis. Evidence: 10/10. Source: PMID 33310085. Typical Risk.
Cancer & Oncology
Gastrointestinal Cancers
Liver Cancer. Evidence: 10/10. Source: PMID 34902334. Typical Risk.
Cardiovascular & Metabolic
Gout & Uric Acid
Gout. Evidence: 10/10. Source: PMID 33832965. ~1.14x Higher Risk.
Pharmacogenomics
Chemotherapy Response
Chemotherapy Liver Damage. Evidence: 10/10. Source: PMID 28090653. Typical Risk.
Showing effects for C/G genotype
Fatty Liver Disease. Evidence: 10/10. Source: PMID 21423719. ~1.66x Higher Risk.
Liver Fat. Evidence: 10/10. Source: PMID 32247823. Increased.
Liver Cirrhosis. Evidence: 10/10. Source: PMID 33310085. Increased Risk.
Liver Cancer. Evidence: 10/10. Source: PMID 34902334. Increased Risk.
Gout. Evidence: 10/10. Source: PMID 33832965. Typical Risk.
Chemotherapy Liver Damage. Evidence: 10/10. Source: PMID 28090653. Increased Risk.
Showing effects for G/G genotype
Fatty Liver Disease. Evidence: 10/10. Source: PMID 21423719. Significantly Higher.
Liver Fat. Evidence: 10/10. Source: PMID 32247823. Highly Increased.
Liver Cirrhosis. Evidence: 10/10. Source: PMID 33310085. ~2.19x Higher Risk.
Liver Cancer. Evidence: 10/10. Source: PMID 34902334. ~1.41x Higher Risk.
What this genotype means for the people who carry it
Sample genotype: CC (Homozygous)
Having two copies of the C allele represents the typical genetic baseline for liver fat metabolism [1]. The functional PNPLA3 protein efficiently breaks down triglycerides and mobilizes lipids out of liver cells, preventing fat accumulation [2]. Consequently, individuals with this genotype have a significantly lower risk of non-alcoholic fatty liver disease (NAFLD) and liver cirrhosis compared to G allele carriers [1] [3]. They also show a lower risk of liver damage when undergoing certain chemotherapy treatments [4]. However, this genotype is associated with a slightly higher risk of developing gout due to elevated uric acid levels [5].
Typical liver fat levels; Lower risk of fatty liver disease; Slightly higher risk of gout.
Sample genotype: CG (Heterozygous)
Carrying one copy of the G allele alters the structure of the PNPLA3 protein, causing it to accumulate on lipid droplets and impairing triglyceride breakdown [1]. This leads to a moderate increase in liver fat content and elevates the risk of non-alcoholic fatty liver disease (NAFLD) [2]. The risk of progressing to liver fibrosis, cirrhosis, and liver cancer is also moderately increased [3] [4]. Additionally, this genotype is associated with a higher susceptibility to liver toxicity and elevated liver enzymes during chemotherapy treatments [5]. On the other hand, this genotype is associated with a lower risk of developing gout compared to CC carriers [6].
Elevated liver fat accumulation; Moderately increased risk of fatty liver disease; Higher risk of chemotherapy-induced liver toxicity.
Sample genotype: GG (Homozygous)
Having two copies of the G allele leads to a pronounced accumulation of the mutated PNPLA3 protein on lipid droplets, severely restricting the liver's ability to mobilize and clear fats [1]. This results in a substantial increase in liver fat content, often up to twofold higher than in CC carriers [2]. Consequently, individuals with this genotype face a significantly elevated risk of developing non-alcoholic fatty liver disease (NAFLD) and progressing to liver cirrhosis [2] [3]. The risk of developing liver cancer is also notably higher [4]. Furthermore, this genotype is linked to a higher risk of severe liver damage and elevated liver enzymes when treated with certain chemotherapy drugs [5]. However, it offers relative protection against gout [6].
High liver fat accumulation; Significantly increased risk of fatty liver disease and cirrhosis; Higher risk of chemotherapy-induced liver toxicity.
Variants with shared genetic architecture
rs3747207 · PNPLA3 Gene · Chr 22 · Fatty Liver Risk
rs738408 · PNPLA3 Gene · Chr 22 · Fatty Liver Risk
rs2896019 · PNPLA3 Gene · Chr 22 · Liver Disease Risk
PNPLA3 expression and its impact on the liver: current perspectives.
Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis.
The PNPLA3 I148M variant modulates the fibrogenic phenotype of human hepatic stellate cells.
Content updated August 2026.
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