rs2268797 — SRD5A2 SRD5A2 intronic variant

SRD5A2 rs2268797 — A Haplotype Window into 5-Alpha-Reductase Activity

Every man's reproductive biology depends on a precise balance between testosterone and dihydrotestosterone (DHT)¹¹ testosterone and dihydrotestosterone (DHT)
DHT is 3–10 times more potent than testosterone at the androgen receptor; it is the dominant androgen driving prostate growth, seminal vesicle development, and hair follicle sensitivity. The enzyme that makes DHT — steroid 5-alpha-reductase type 2, encoded by SRD5A2 — is most active in the prostate, genital skin, and seminal vesicles. Variants across the SRD5A2 gene collectively shape how much of this conversion occurs, and rs2268797 is one of several intragenic markers that together define the haplotype architecture of this locus.

Unlike the coding-region SRD5A2 variants that directly alter the enzyme's amino acid sequence (most notably V89L rs523349 and A49T rs9282858), rs2268797 sits within an intron — a non-coding segment of the gene. Its biological relevance comes primarily from its role as a haplotype tag: it travels with particular combinations of nearby variants that together influence 5-alpha-reductase function, and in population studies it has been associated with modest differences in sperm motility, which likely reflect the activity of the haplotype background it marks rather than a direct functional effect of the intronic change itself.

The Mechanism

SRD5A2 encodes steroid 5-alpha-reductase type 2, a microsomal enzyme active at acidic pH that irreversibly reduces the double bond at the 4,5 position of testosterone²² irreversibly reduces the double bond at the 4,5 position of testosterone
The reaction produces 5α-DHT and requires NADPH as cofactor; the reaction is essentially irreversible under physiological conditions, which is why 5-alpha-reductase inhibitors must be taken continuously to yield DHT. In the male reproductive system, this conversion is essential for: normal development of the external genitalia during fetal life, prostate growth and secretory function, seminal vesicle development, and direct effects on spermatogenesis via Sertoli cell androgen signaling.

rs2268797 is a C-to-T transition in intron 1 of SRD5A2. The C allele appears at 42–50% frequency in most populations and serves as the GRCh38 reference base at this position. Because intronic variants can influence splicing efficiency, mRNA stability, or serve as linkage disequilibrium proxies for nearby functional variants, their biological context requires interpreting them at the haplotype level rather than in isolation. In the context of a gene with several well-characterized coding variants, intronic tagging SNPs like rs2268797 capture haplotype-level variation in enzyme expression and activity that may not be fully explained by coding variants alone.

The Evidence

The direct evidence for rs2268797 is limited to two primary studies, with additional use as a haplotype marker in a case study of rare SRD5A2 deficiency.

Peters et al. (2010)³³ Peters et al. (2010)
Analysis of polymorphisms in the SRD5A2 gene and semen parameters in Estonian men. Journal of Andrology, 2010;31(4):372–8 examined five SRD5A2 SNPs — including rs2268797 — in 132 infertile men and 211 normozoospermic controls (n=343 total). The overall finding was that the SRD5A2 variants "exhibit no adverse effect on semen parameters" in terms of sperm concentration, FSH, or testosterone. However, among normozoospermic men, carriers of the minor allele at rs2268797 (the C allele in this European Estonian cohort, where T is the major allele) had a significantly higher proportion of progressively motile spermatozoa compared to major homozygotes — a finding replicated across most of the five SNPs studied. The authors attributed this to haplotype-level differences in 5-alpha-reductase activity affecting DHT's direct role in sperm maturation in the epididymis.

Zhao et al. (2012)⁴⁴ Zhao et al. (2012)
Variants in the SRD5A2 gene are associated with quality of semen. Molecular Medicine Reports, 2012;6(3):639–44 studied rs2268797 alongside four other SRD5A2 variants in 708 Chinese infertile men. Unlike the Estonian study, rs2268797 did not emerge as independently significant in this cohort; the significant associations were limited to rs13395648 (semen volume) and rs632148 (sperm motility). The ethnic difference in findings is consistent with the known population stratification of SRD5A2 haplotypes — haplotype blocks tagged by rs2268797 differ in their frequency and linkage disequilibrium structure between European and East Asian populations.

Avendaño et al. (2020)⁵⁵ Avendaño et al. (2020)
5α-Reductase type 2 deficiency in Andean Venezuelan families. Annals of Human Genetics, 2020;84(2):151–60 used rs2268797 as one of five intragenic SNPs to construct SRD5A2 haplotypes in families segregating 46,XY disorder of sex development caused by complete SRD5A2 loss-of-function mutations. This confirmed rs2268797's utility as a haplotype-phasing marker in population genetics studies of this locus, though it demonstrated no direct pathogenic role.

The broader SRD5A2 pharmacogenomics literature is relevant context: Makridakis et al. (2000)⁶⁶ Makridakis et al. (2000)
Biochemical and pharmacogenetic dissection of SRD5A2. Pharmacogenetics, 2000;10(5):407–13 demonstrated up to 60-fold variation in finasteride inhibition efficiency across SRD5A2 missense variants, underscoring how sensitively the enzyme's activity and drug response depends on its exact genetic configuration — a configuration for which haplotype-tagging SNPs like rs2268797 provide partial information.

Practical Implications

For most men, this variant is informative primarily as context: it indicates which SRD5A2 haplotype background your functional coding variants (V89L, A49T) sit on, which matters for interpreting your overall 5-alpha-reductase activity profile. If you are concerned about male fertility, prostate health, or response to 5-alpha-reductase inhibitors (finasteride, dutasteride), the coding variants rs523349 (V89L) and rs9282858 (A49T) carry most of the directly functional information at this gene.

For men with two copies of the C allele (CC genotype), the data from the Estonian study suggest this haplotype background may be associated with somewhat lower progressive sperm motility compared to T-allele carriers in European populations, where the C allele is the minor haplotype. The effect is modest and only detected in normozoospermic men — it does not appear to increase the risk of frank infertility.

Interactions

rs2268797 is in linkage disequilibrium with the two best-characterized SRD5A2 coding variants: rs523349 (V89L, the most common functional variant, reducing enzyme activity by ~30%) and rs9282858 (A49T, a rarer variant with larger effect on both enzyme activity and prostate cancer risk). Haplotype analysis across rs2268797, rs523349, and rs9282858 captures a richer picture of SRD5A2 activity than any single variant alone. In the Avendaño et al. study, the combination of these intragenic SNPs was sufficient to phase disease-causing mutations onto specific chromosomal backgrounds, confirming that they tag largely non-overlapping haplotypes.

For men receiving finasteride or dutasteride (for male pattern baldness or BPH), the SRD5A2 haplotype background — partially tagged by rs2268797 — influences enzyme-inhibitor binding affinity. However, clinical dosing of these drugs does not yet incorporate haplotype information, and the practical implication is mainly to be aware that suboptimal responses may have a pharmacogenomic basis worth discussing with a prescriber.