rs700519 — CYP19A1 Arg264Cys

CYP19A1 Arg264Cys — An Aromatase Coding Variant With Mixed Population Evidence

Aromatase¹¹ Aromatase
the enzyme encoded by CYP19A1 that converts androgens to estrogens in the final step of estrogen biosynthesis is expressed in the ovaries, adipose tissue, placenta, bone, breast, and brain. It is the only enzyme in vertebrates capable of producing estrogens, making it central to reproductive function, bone metabolism, and hormone balance throughout the lifespan. The rs700519 variant causes a non-synonymous substitution of arginine by cysteine at position 264 of the aromatase protein — a missense change in exon 7. This variant sits in a region of the enzyme with structural significance, and functional studies suggest the Cys264 protein may behave differently from the wild-type Arg264 form, though in vivo evidence across populations is inconsistent.

The Mechanism

The p.Arg264Cys substitution replaces a positively charged arginine residue with a smaller, thiol-bearing cysteine in the substrate-binding region of the aromatase enzyme. Arg264 is thought to contribute to the electrostatic environment of the active site, and its replacement may alter substrate affinity or catalytic efficiency²² Arg264 is thought to contribute to the electrostatic environment of the active site, and its replacement may alter substrate affinity or catalytic efficiency. In an in vitro transfection study using human embryonic kidney 293 cells³³ in vitro transfection study using human embryonic kidney 293 cells
HEK293 cells do not normally express CYP19A1, making this a clean system for comparing allele function, the Cys264 variant protein showed increased conversion of androstenedione to estrogen compared with the wild-type Arg264 form (p<0.001), suggesting enhanced catalytic activity. This directionally supports the hypothesis that Cys264 carriers may have somewhat increased aromatase-mediated estrogen synthesis — but the in vivo effect may be tissue- or context-specific.

Because CYP19A1 is on the minus (coding) strand, papers describing the variant in coding-strand notation call it C>T (C=Arg264, T=Cys264). In genome files (including 23andMe and WGS), alleles appear on the plus strand as G (reference) and A (risk).

The Evidence

The primary study establishing an association between rs700519 and reproductive function is Wang et al. 2011 in Molecular Human Reproduction⁴⁴ Wang et al. 2011 in Molecular Human Reproduction
A common polymorphism in the human aromatase gene alters the risk for polycystic ovary syndrome and modifies aromatase activity in vitro. Mol Hum Reprod 17:386-391. Genotyping 1,078 participants (PCOS cases and controls), they found the Arg264Cys T allele associated with PCOS risk (uncorrected p=0.004, Bonferroni-corrected p=0.02). The in vitro component showed increased aromatase activity in cells expressing the Cys264 variant (p<0.001 for androstenedione-to-estrogen conversion).

A 2017 Chinese population-based study of 293 PCOS patients undergoing ART found the CC genotype (i.e., wild-type GG on the plus strand) and elevated BMI were associated with unfavorable pregnancy outcomes⁵⁵ the CC genotype (i.e., wild-type GG on the plus strand) and elevated BMI were associated with unfavorable pregnancy outcomes
Dou et al. 2017, Kaohsiung J Med Sci 33:558-566, while the CT+TT genotype group (AG+AA on plus strand) showed higher pregnancy rates. This suggests the Cys264 variant may modulate ovarian response to gonadotropin stimulation in PCOS.

Not all populations show this association. A study of 250 PCOS cases and 250 controls from North India found no significant difference in rs700519 genotype distribution (p=0.635)⁶⁶ A study of 250 PCOS cases and 250 controls from North India found no significant difference in rs700519 genotype distribution (p=0.635)
Kaur et al. 2018, J Assist Reprod Genet, consistent with several South Indian studies. A study of 1,022 elderly Caucasian women found no association between Arg264Cys and circulating estradiol, bone density, or fracture risk⁷⁷ A study of 1,022 elderly Caucasian women found no association between Arg264Cys and circulating estradiol, bone density, or fracture risk
Wang et al. 2011, BMC Med Genet, where the T allele frequency was only 2.4%, limiting power for any AA homozygote analysis.

Beyond reproductive health, a 2007 Shanghai case-control study (1,040 endometrial cancer cases, 1,031 controls) found a multiplicative interaction between rs700519 and BMI among postmenopausal women (p=0.01)⁸⁸ a 2007 Shanghai case-control study (1,040 endometrial cancer cases, 1,031 controls) found a multiplicative interaction between rs700519 and BMI among postmenopausal women (p=0.01)
Tao et al. 2007, Cancer Epidemiol Biomark Prev 16:943-950, with stronger genotype effects in heavier women. A meta-analysis of 9 case-control studies found the rs700519 AA genotype inversely associated with breast cancer risk in dominant and allelic models⁹⁹ meta-analysis of 9 case-control studies found the rs700519 AA genotype inversely associated with breast cancer risk in dominant and allelic models
Lv et al. 2021, Genet Test Mol Biomark (allelic OR 0.84, 95% CI 0.75-0.93). A 2006 Chinese breast cancer cohort found Cys/Cys homozygotes had hazard ratio 2.2 (95% CI 1.2-4.1) for worse disease-free survival¹⁰¹⁰ 2006 Chinese breast cancer cohort found Cys/Cys homozygotes had hazard ratio 2.2 (95% CI 1.2-4.1) for worse disease-free survival
Long et al. 2006, Cancer Epidemiol Biomarkers Prev, though the AA genotype is exceptionally rare in European populations.

Practical Actions

The most relevant implication for women in reproductive years is potential aromatase activity enhancement in the ovaries. If local aromatase activity in granulosa cells is increased in Cys264 carriers, ovarian estrogen synthesis from androgen precursors may be more efficient, contributing to altered estrogen-androgen balance. The ART data further suggest that in women undergoing ovarian stimulation for IVF, genotype may influence gonadotropin response in PCOS. Letrozole, which inhibits aromatase to induce ovulation, is the standard-of-care first-line agent for anovulatory PCOS; carriers with increased baseline aromatase activity may have different dosing requirements, though prospective pharmacogenomics data for rs700519 specifically are limited.

The BMI-interaction finding in endometrial cancer data is a reminder that adipose-derived aromatase is the primary estrogen source postmenopausally, and variants that increase enzyme activity may have amplified effects in the context of excess adipose tissue.

Interactions

Rs700519 and rs700518 are both CYP19A1 coding/functional variants that may influence total aromatase activity through different mechanisms (Cys264 increases catalytic activity; rs700518 Val80 affects expression levels). Women carrying risk genotypes at both loci may have compounded effects on ovarian estrogen synthesis. The clinical direction of that interaction — and whether it matters for fertility outcomes or hormone-sensitive cancer risk — deserves prospective study. See related_snps for other CYP19A1 variants (rs10046, rs4646, rs1062033) that form haplotypes with rs700519.