rs1993116 — CYP2R1 CYP2R1 rs1993116

Intronic regulatory variant in CYP2R1 that reduces hepatic vitamin D 25-hydroxylase expression, lowering the rate of vitamin D activation and increasing susceptibility to vitamin D insufficiency

See your personal result for CYP2R1

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

CYP2R1 rs1993116 — Your Vitamin D Activation Throttle

The CYP2R1 gene11 CYP2R1 gene
Cytochrome P450 family 2 subfamily R member 1; encodes the primary liver enzyme responsible for converting vitamin D3 (cholecalciferol) into 25-hydroxyvitamin D, the storage and transport form measured in blood tests is the gatekeeper of vitamin D activation. Before vitamin D can do anything useful in the body, the liver must convert it from its ingested or sun-derived form into 25-hydroxyvitamin D (25(OH)D)22 25-hydroxyvitamin D (25(OH)D)
Also called calcidiol; this is the form measured in standard blood tests and the main circulating vitamin D metabolite. The kidneys then convert it further into calcitriol, the active hormone. CYP2R1 performs this critical first hydroxylation step. rs1993116 is an intronic variant that influences how efficiently CYP2R1 is expressed — people carrying the G allele produce less of this enzyme, leaving more vitamin D unconverted.

The Mechanism

rs1993116 sits within an intron of CYP2R1 on chromosome 11 (GRCh38: chr11:14,888,688). Because CYP2R1 is on the minus strand, the variant is described using plus-strand alleles in genome files: A (the minor, protective allele) versus G (the major, risk allele). The intronic position suggests the variant affects splicing efficiency or enhancer activity33 splicing efficiency or enhancer activity
Intronic variants can alter the binding of splicing regulatory proteins or transcription factors, changing the amount of functional mRNA produced without changing the protein sequence itself rather than the enzyme's catalytic activity directly. The net effect is that G allele carriers produce less CYP2R1 protein and therefore convert less dietary and sun-derived vitamin D into its measurable 25(OH)D form.

This variant is in partial linkage disequilibrium with rs10741657, the more commonly cited CYP2R1 GWAS locus, but the two variants are not perfectly correlated — each captures some independent variation in CYP2R1 expression. In European Americans, rs1993116 has been reported as the most strongly associated CYP2R1 variant with 25(OH)D levels44 most strongly associated CYP2R1 variant with 25(OH)D levels
Batai et al. 2014, Human Genetics — rs1993116 showed the strongest CYP2R1 signal in European Americans, while rs12794714 was the leading variant in African Americans, demonstrating that the causal architecture differs by ancestry.

The Evidence

The clearest functional evidence comes from a 2019 Japanese study55 2019 Japanese study
Arai T et al. Association of vitamin D levels and vitamin D-related gene polymorphisms with liver fibrosis in patients with biopsy-proven nonalcoholic fatty liver disease. Dig Liver Dis, 2019 of 229 NAFLD patients in which non-AA genotype at rs1993116 emerged as an independent predictor of vitamin D deficiency (≤20 ng/mL) in multivariate analysis — meaning the association held even after controlling for sun exposure, BMI, season, and other confounders.

A 2018 Egyptian study66 2018 Egyptian study
Sedky NK et al. Genetic Variants of CYP2R1 Are Key Regulators of Serum Vitamin D Levels and Incidence of Myocardial Infarction in Middle-Aged Egyptians. Curr Pharm Biotechnol, 2018 in 323 subjects found that AG/GG genotypes at rs1993116 defined the high-risk grouping for lower serum 25(OH)D and elevated myocardial infarction risk (combined OR 14.1 for all three high-risk CYP2R1 genotypes together).

In a Chinese rural population, Wang et al. (2018)77 Wang et al. (2018)
Wang Y et al. Triangular relationship between CYP2R1 gene polymorphism, serum 25(OH)D3 levels and T2DM in a Chinese rural population. Gene, 2018 found that the non-AA genotype carried 64% higher odds of type 2 diabetes (OR 1.64, 95% CI 1.09–2.46, P=0.048) in 794 subjects, consistent with the established link between vitamin D insufficiency and insulin resistance.

Robien et al. (2013)88 Robien et al. (2013)
Robien K et al. Genetic and environmental predictors of serum 25-hydroxyvitamin D concentrations among middle-aged and elderly Chinese in Singapore. Br J Nutr, 2013 replicated the association in 504 Chinese Singaporeans, confirming that rs1993116 and rs10741657 both contribute independently to circulating 25(OH)D levels across diverse populations.

A 2013 analysis of 5,604 hepatitis C patients found that genotypes associated with reduced 25(OH)D via CYP2R1 variants trended toward higher hepatocellular carcinoma risk (OR 1.13, P=0.07)99 (OR 1.13, P=0.07)
Lange CM et al. Genetic analyses reveal a role for vitamin D insufficiency in HCV-associated hepatocellular carcinoma development. PLoS One, 2013, further illustrating the downstream consequences of genetically lower vitamin D.

Practical Actions

The core intervention is the same regardless of which CYP2R1 variant is limiting your 25(OH)D production: increase the substrate (vitamin D3 input) to compensate for slower conversion. G allele carriers typically need higher supplementation doses than the general population to achieve the same circulating 25(OH)D level. Testing serum 25(OH)D is the only reliable way to calibrate the right dose — an optimal level is generally considered 40–60 ng/mL (100–150 nmol/L).

Magnesium is a cofactor for both CYP2R1 and the downstream CYP27B1 hydroxylase; deficiency impairs vitamin D conversion independently of genotype, so GG carriers have extra reason to ensure adequate magnesium intake.

Interactions

rs1993116 interacts with rs10741657, the other major CYP2R1 locus. Both variants influence CYP2R1 expression and are partially correlated; carriers of risk alleles at both loci have compounded 25-hydroxylation impairment.

Beyond CYP2R1, the vitamin D pathway involves several other gene variants already profiled: rs12785878 (DHCR7/NADSYN1, skin synthesis), rs4588 and rs7041 (GC/VDBP, transport), rs2228570 (VDR FokI, receptor sensitivity), and rs6013897 (CYP24A1, degradation). Individuals carrying risk alleles across two or more of these loci face compounded insufficiency risk; large GWAS data showed 2.47-fold increased odds of vitamin D insufficiency for the highest multi-locus risk score.

Nutrient Interactions

vitamin D3 (cholecalciferol) impaired_conversion

Genotype Interpretations

What each possible genotype means for this variant.

AA High Hydroxylation Capacity Beneficial

Higher CYP2R1 expression — efficient vitamin D 25-hydroxylation

CYP2R1 is the dominant hepatic vitamin D 25-hydroxylase. The A allele at rs1993116 is associated with greater CYP2R1 activity, meaning that for a given vitamin D3 input (from sun exposure or supplements), AA individuals produce more 25(OH)D than AG or GG carriers. This does not guarantee vitamin D sufficiency — sun avoidance, dark skin, high BMI, or very low dietary intake can override the genetic advantage — but it does mean your liver is not the limiting step in vitamin D metabolism.

Your overall vitamin D status will still depend on the other pathway variants (GC transport, VDR receptor sensitivity, CYP24A1 degradation rate), lifestyle factors, and supplementation.

AG Reduced Hydroxylation Intermediate

One G allele — moderately reduced vitamin D activation capacity

In the additive model for this variant, each G allele incrementally reduces CYP2R1-mediated 25-hydroxylation. AG carriers occupy the middle of the distribution — they convert vitamin D3 less efficiently than AA homozygotes but more efficiently than GG homozygotes. Population studies consistently find AG genotype associated with intermediate serum 25(OH)D levels.

The practical implication is that AG carriers are more sensitive to lifestyle factors that reduce vitamin D input: limited sun exposure, sunscreen use, northern latitude, dark skin, and low dietary intake each compound the genetic limitation. Correcting these factors or supplementing proactively can fully compensate for the reduced conversion rate.

GG Low Hydroxylation Capacity Reduced

Homozygous G allele — lowest CYP2R1 expression, highest vitamin D insufficiency risk

Homozygous GG individuals have the lowest CYP2R1-driven 25-hydroxylation rate. Multiple population studies identify non-AA (particularly GG) genotype as independently associated with vitamin D deficiency after controlling for sun exposure, season, BMI, and other confounders. In the Arai et al. 2019 NAFLD cohort, non-AA genotype was significantly associated with 25(OH)D ≤20 ng/mL in multivariate analysis. In an Egyptian MI cohort, the AG/GG risk grouping contributed to substantially elevated cardiovascular risk.

The reduced enzyme output means GG individuals need meaningfully higher vitamin D3 input to achieve the same circulating 25(OH)D as AA carriers. This also means GG individuals respond less robustly to low-dose supplementation (400–800 IU/day) and are more likely to remain insufficient even while nominally supplementing.

Serum 25(OH)D is the gold standard for assessing actual status — genotype alone predicts risk but not outcome, because lifestyle, body weight, and sun exposure still contribute substantially.