What you carry at this position in your DNA and what research says about it.
Gallstone and Liver Risk: 8/10 evidence, 70 publications.
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Sample genotype (not yours): C/C
Typical Gallstone Risk and Higher HDL
Maintaining the typical threonine amino acid preserves normal HNF4A protein function. This results in a baseline risk for gallstones and diabetes, alongside slightly higher HDL cholesterol levels.
What this genotype means: Typical baseline risk for gallstones and gallbladder issues; Standard insulin secretion and typical type 2 diabetes risk; Slightly higher circulating HDL and LDL cholesterol levels.
Sample genotype (not yours): C/T
Increased Gallstone and Diabetes Risk
Carrying one copy of the isoleucine variant slightly reduces HNF4A protein activity. This increases the susceptibility to gallstones, type 2 diabetes, and pregnancy-related liver issues.
What this genotype means: Moderately elevated risk of developing gallstones; Slightly increased susceptibility to type 2 diabetes; Slightly lower LDL and total cholesterol levels.
Sample genotype (not yours): T/T
Higher Gallstone and Diabetes Risk
Carrying two copies of the isoleucine variant further reduces HNF4A activity. This significantly increases the risk of gallstones, type 2 diabetes, and gestational liver complications.
What this genotype means: Significantly elevated risk of gallstones and gallbladder inflammation; Increased susceptibility to type 2 diabetes and gestational liver issues; Lowest levels of circulating LDL and total cholesterol.
Gene function and biological role
Gene Function: The HNF4A gene encodes hepatocyte nuclear factor 4 alpha, a master transcription factor primarily active in the liver, gut, and pancreatic beta cells [1]. It plays a critical role in regulating the expression of genes involved in lipid metabolism, glucose homeostasis, and bile acid synthesis [2]. Severe, rare mutations in this gene are known to cause maturity-onset diabetes of the young type 1 (MODY1), a rare form of monogenic diabetes [3]. Additionally, HNF4A coordinates the transport of cholesterol and the secretion of insulin in response to glucose [4].
Variant Impact: This missense variant, rs1800961, alters a single amino acid in the HNF4A protein from threonine to isoleucine at position 117 [1]. This structural change slightly reduces the transcription factor's activity, impacting downstream metabolic pathways in the liver and pancreas [1]. While ClinVar classifies this variant as benign for causing rare monogenic diabetes, large-scale studies show it acts as a common risk modifier for complex metabolic traits [5]. Specifically, the altered protein function shifts the balance of cholesterol secretion into bile, which directly influences the risk of gallstones and liver conditions [6].
Key Insight: The same genetic variant that increases the risk of gallstones and type 2 diabetes actually lowers circulating LDL and total cholesterol levels.
Location: HNF4A. Chromosome 20 · 20q13.12 · 44.4 Mb
Estimated prevalence by population
Global 95.1%; European 94.1%; African 98.8%; East Asian 97.5%; South Asian 94.4%; Americas 90.1%; Ashkenazi 95.0%; Finnish 91.9%; Middle Eastern 100.0%; Amish 99.1%.
Estimated CC genotype frequency.
Global 4.9%; European 5.8%; African 1.2%; East Asian 2.5%; South Asian 5.5%; Americas 9.7%; Ashkenazi 4.9%; Finnish 8.0%; Middle Eastern 0.0%; Amish 0.9%.
Estimated CT genotype frequency.
Global 0.1%; European 0.1%; African < 0.1%; East Asian < 0.1%; South Asian 0.1%; Americas 0.3%; Ashkenazi 0.1%; Finnish 0.2%; Middle Eastern 0.0%; Amish < 0.1%.
Estimated TT genotype frequency.
Showing effects for C/C genotype
Organ Systems
Digestive & Gut Disorders
Gallstones. Evidence: 10/10. Source: PMID 34594039. Typical Risk.
Liver Function & Disease
Liver Disease. Evidence: 8/10. Source: PMID 40069456. Typical Risk.
Cardiovascular & Metabolic
Diabetes & Glycemic Traits
Type 2 Diabetes. Evidence: 10/10. Source: PMID 29632382. Typical Risk.
Lipids & Cholesterol
HDL Cholesterol. Evidence: 10/10. Source: PMID 19060906. Slightly Higher.
LDL Cholesterol. Evidence: 10/10. Source: PMID 27286809. Slightly Higher.
Endocrine & Reproductive
Pregnancy & Birth Complications
Pregnancy Cholestasis. Evidence: 7/10. Source: PMID 35977952. Typical Risk.
Showing effects for C/T genotype
Gallstones. Evidence: 10/10. Source: PMID 34594039. ~1.34x Increased Risk.
Liver Disease. Evidence: 8/10. Source: PMID 40069456. ~1.82x Increased Risk.
Type 2 Diabetes. Evidence: 10/10. Source: PMID 29632382. Increased Risk.
HDL Cholesterol. Evidence: 10/10. Source: PMID 19060906. Slightly Lower.
LDL Cholesterol. Evidence: 10/10. Source: PMID 27286809. Slightly Lower.
Pregnancy Cholestasis. Evidence: 7/10. Source: PMID 35977952. ~2.06x Increased Risk.
Showing effects for T/T genotype
Gallstones. Evidence: 10/10. Source: PMID 34594039. Increased Risk.
Liver Disease. Evidence: 8/10. Source: PMID 40069456. Increased Risk.
Pregnancy Cholestasis. Evidence: 7/10. Source: PMID 35977952. Increased Risk.
What this genotype means for the people who carry it
Sample genotype: CC (Homozygous)
Preserving the reference threonine amino acid ensures that the HNF4A transcription factor operates at its standard functional capacity [1]. Standard protein activity maintains normal bile acid synthesis and cholesterol transport in the liver, which keeps the risk of developing gallstones at a typical baseline level [2]. Similarly, pancreatic beta cells secrete insulin normally, avoiding the elevated risk of type 2 diabetes associated with the variant form of the gene [3]. On the lipid side, this genotype is associated with slightly higher levels of HDL cholesterol, which is generally considered favorable for cardiovascular health [4]. However, it also correlates with slightly higher levels of LDL and total cholesterol [5]. Overall, this genetic profile represents the most common metabolic baseline in the global population.
Typical baseline risk for gallstones and gallbladder issues; Standard insulin secretion and typical type 2 diabetes risk; Slightly higher circulating HDL and LDL cholesterol levels.
Sample genotype: CT (Heterozygous)
Inheriting one copy of the isoleucine variant introduces a structural change that mildly reduces the regulatory activity of the HNF4A protein [1]. In the liver, this altered function shifts cholesterol transport and bile composition, leading to a higher likelihood of cholesterol crystallization and gallstone formation [2]. The risk of developing gallstones is elevated by approximately 34% compared to the common genotype [2]. Additionally, the variant affects insulin secretion pathways in the pancreas, contributing to a moderately increased risk of type 2 diabetes [3]. Pregnant individuals with this genotype also face a higher risk of intrahepatic cholestasis, a liver condition characterized by slowed bile flow [4]. Interestingly, this metabolic shift results in slightly lower circulating levels of LDL and total cholesterol [5]. Despite the minor lipid benefit, the overall profile points to elevated metabolic and biliary risks.
Moderately elevated risk of developing gallstones; Slightly increased susceptibility to type 2 diabetes; Slightly lower LDL and total cholesterol levels.
Sample genotype: TT (Homozygous)
Inheriting two copies of the isoleucine variant leads to a more pronounced reduction in HNF4A transcription factor activity [1]. With both copies altered, the liver's ability to regulate bile acid synthesis and cholesterol secretion is significantly modified, leading to a higher rate of gallstone crystallization [2]. This genotype is strongly associated with an increased risk of gallstones and related gallbladder inflammation [2]. In the pancreas, reduced HNF4A activity impairs glucose-stimulated insulin secretion, elevating the risk of type 2 diabetes [3]. There is also a substantial increase in the risk of intrahepatic cholestasis of pregnancy, a condition that requires careful monitoring [4]. On the other hand, circulating levels of LDL and total cholesterol are at their lowest with this genotype [5]. However, the marked increase in biliary and diabetic risks outweighs this minor lipid reduction, making proactive lifestyle management highly beneficial.
Significantly elevated risk of gallstones and gallbladder inflammation; Increased susceptibility to type 2 diabetes and gestational liver issues; Lowest levels of circulating LDL and total cholesterol.
Variants with shared genetic architecture
rs2071197 · HNF4A Gene · Chr 20 · Type 2 Diabetes Risk
rs10401969 · SUGP1 Gene · Chr 19 · Cholesterol and Liver Risk
rs11887534 · ABCG8 Gene · Chr 2 · Gallstone Risk
A cross-population atlas of genetic associations for 220 human phenotypes.
Biological, clinical and population relevance of 95 loci for blood lipids.
Content updated August 2026.
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