What you carry at this position in your DNA and what research says about it.
Obesity and Weight Risk: 8/10 evidence, 36 publications.
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Sample genotype (not yours): A/A
Typical Obesity and Weight Risk
This genotype is associated with standard appetite regulation and a typical body mass index. Baseline metabolic health is generally easier to maintain.
What this genotype means: Standard appetite regulation; Typical body fat distribution.
Sample genotype (not yours): A/G
Slightly Increased Obesity Risk
Carrying one copy of the variant is linked to a slightly higher average body mass index.
What this genotype means: Slightly higher baseline appetite; Increased tendency to store abdominal fat.
Sample genotype (not yours): G/G
Higher Obesity and Weight Risk
Carrying two copies of the variant is linked to a higher average body mass index and increased abdominal fat.
What this genotype means: Higher risk of elevated body mass index; Greater accumulation of visceral fat; Slightly elevated liver enzymes under metabolic stress.
Gene function and biological role
Gene Function: The SH2B1 gene encodes an essential adaptor protein that plays a critical role in cellular signaling pathways [1]. It acts as a key regulator of both leptin and insulin signaling, which are crucial for maintaining energy balance and glucose homeostasis [1]. In the brain, particularly within the hypothalamus, this protein enhances leptin receptor signaling to help control appetite and body weight [1]. In peripheral tissues, it facilitates insulin signaling to promote proper glucose uptake and prevent insulin resistance [2]. Animal studies show that a complete lack of this gene leads to severe overeating, morbid obesity, and type 2 diabetes [1].
Variant Impact: The rs7498665 variant is a missense mutation in the SH2B1 gene that alters the amino acid at position 484 from threonine to alanine [1]. A substitution of this nature occurs in a highly conserved region of the protein, potentially altering its interaction with signaling partners [2]. Although the single amino acid substitution is not enough to cause severe monogenic obesity on its own, it significantly influences common, complex weight gain [3]. Large-scale genetic studies have consistently linked this alteration to subtle shifts in body mass index, body fat distribution, and metabolic health [4].
Key Insight: This variant affects how your brain processes leptin, the hormone responsible for signaling fullness, which can subtly influence daily appetite and snacking behavior.
Location: SH2B1. Chromosome 16 · 16p11.2 · 28.9 Mb
Estimated prevalence by population
Global 43.4%; European 36.6%; African 53.3%; East Asian 76.7%; South Asian 59.7%; Americas 34.9%; Ashkenazi 53.3%; Finnish 32.2%; Middle Eastern 59.7%; Amish 57.5%.
Estimated AA genotype frequency.
Global 44.0%; European 47.8%; African 39.4%; East Asian 21.8%; South Asian 35.1%; Americas 48.3%; Ashkenazi 39.4%; Finnish 49.1%; Middle Eastern 35.2%; Amish 36.6%.
Estimated AG genotype frequency.
Global 12.5%; European 15.6%; African 7.3%; East Asian 1.5%; South Asian 5.2%; Americas 16.7%; Ashkenazi 7.3%; Finnish 18.7%; Middle Eastern 5.2%; Amish 5.8%.
Estimated GG genotype frequency.
Showing effects for A/A genotype
Cardiovascular & Metabolic
Obesity & Body Composition
Obesity. Evidence: 8/10. Source: PMID 19079260. Typical Risk.
Waist Circumference. Evidence: 10/10. Source: PMID 25673412. Typical.
Visceral Fat. Evidence: 8/10. Source: PMID 31501611. Typical.
Organ Systems
Liver Function & Disease
Liver Enzyme Levels. Evidence: 7/10. Source: PMID 38632349. Typical ALT.
Showing effects for A/G genotype
Obesity. Evidence: 8/10. Source: PMID 19079260. Increased Risk.
Waist Circumference. Evidence: 10/10. Source: PMID 25673412. Slightly Higher.
Visceral Fat. Evidence: 8/10. Source: PMID 31501611. Slightly Increased.
Liver Enzyme Levels. Evidence: 7/10. Source: PMID 38632349. Slightly Elevated ALT.
Showing effects for G/G genotype
Obesity. Evidence: 8/10. Source: PMID 19079260. Higher Risk.
Waist Circumference. Evidence: 10/10. Source: PMID 25673412. Higher.
Visceral Fat. Evidence: 8/10. Source: PMID 31501611. Increased.
Liver Enzyme Levels. Evidence: 7/10. Source: PMID 38632349. Elevated ALT.
What this genotype means for the people who carry it
Sample genotype: AA (Homozygous)
Maintaining a typical body mass index and a standard risk of weight-related metabolic issues is highly associated with this genotype [1]. Cellular signaling pathways for leptin and insulin function at baseline levels, supporting normal appetite regulation and energy balance [2]. Large-scale population studies show that people with these genetic markers tend to have lower waist circumferences and less visceral fat compared to those carrying the variant allele [3]. Physical activity and balanced nutrition work efficiently to maintain metabolic health without an added genetic hurdle [4]. Additionally, standard insulin sensitivity helps protect cardiovascular health and maintains normal liver enzyme levels [5].
Standard appetite regulation; Typical body fat distribution.
Sample genotype: AG (Heterozygous)
An elevated likelihood of experiencing a higher body mass index is associated with this single-copy variant [1]. Leptin signaling in the brain may be slightly less efficient, which can subtly influence appetite and food intake [2]. Research indicates a higher likelihood of accumulating fat around the waist and within visceral organs [3]. Although this genetic nudge raises the baseline risk for obesity, lifestyle factors play a massive role in determining actual outcomes [4]. Higher glucose levels can compound the genetic risk for weight gain [5].
Slightly higher baseline appetite; Increased tendency to store abdominal fat.
Sample genotype: GG (Homozygous)
The presence of two alanine alleles is associated with the highest genetic risk for elevated body mass index and obesity at this locus [1]. Reduced efficiency in leptin and insulin signaling pathways often results from this double amino acid substitution [2]. This reduction often manifests as increased appetite, higher body fat percentage, and a greater accumulation of visceral fat around internal organs [3]. Clinical studies show that these genetic factors also correlate with higher levels of liver enzymes like alanine aminotransferase, indicating potential metabolic stress [4].
Higher risk of elevated body mass index; Greater accumulation of visceral fat; Slightly elevated liver enzymes under metabolic stress.
Variants with shared genetic architecture
rs7359397 · SH2B1 Gene · Chr 16 · Metabolic and Weight Risk
rs4788102 · SH2B1 Gene · Chr 16 · Weight and Obesity Risk
rs3817334 · MTCH2 Gene · Chr 11 · Obesity and BMI Risk
The SH2B gene is associated with serum leptin and body fat in normal female twins.
Content updated August 2026.
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