rs7594951 — SRD5A2 SRD5A2 intron 4 regulatory variant

Deep intronic variant in the testosterone-to-DHT converting enzyme; the minor T allele is associated with higher serum DHT levels, with implications for androgenetic alopecia severity, prostate growth, and response to 5-alpha-reductase inhibitors

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SRD5A2 rs7594951 — A Regulatory Variant Tuning DHT Production

The SRD5A2 gene encodes steroid 5-alpha-reductase type 2, the enzyme that converts testosterone into dihydrotestosterone (DHT) — the androgen driving prostate growth, scalp hair loss, and male external genital development in utero. Variants in SRD5A2 that alter enzyme activity or expression can shift how much DHT an individual produces throughout life, with downstream effects on androgen-sensitive tissues. The rs7594951 variant lies deep within intron 4 of SRD5A2 on chromosome 2 (GRCh38 position 31,566,723). The SRD5A2 gene runs on the minus strand; in the coding-strand frame this is a G>A change, while in genome files (WGS and consumer chips including 23andMe) it appears as the plus-strand C>T variant described here.

The Mechanism

As an intronic variant, rs7594951 does not alter the SRD5A2 protein sequence directly. Instead, it may affect pre-mRNA splicing, intronic enhancer elements, or mRNA stability — mechanisms known to modify the final amount of functional enzyme produced from a gene. The precise molecular mechanism has not been characterized in published literature, making this a variant of [emerging | an association identified in a single moderately-sized study that requires replication in larger cohorts] evidence status rather than an established functional variant.

SRD5A2 is the dominant 5-alpha-reductase isoform in the prostate, seminal vesicles, epididymis, and fetal external genitalia. Its activity level determines how much DHT is produced locally in androgen-sensitive tissues — and therefore how sensitive those tissues are to androgenic stimulation.

The Evidence

The primary evidence linking rs7594951 to DHT metabolism comes from a 2010 study by Setlur et al. examining 426 Austrian men (205 controls, 221 prostate cancer cases) for variants in DHT-metabolizing genes11 Setlur et al. examining 426 Austrian men (205 controls, 221 prostate cancer cases) for variants in DHT-metabolizing genes
Setlur SR et al. Cancer Epidemiol Biomarkers Prev. 2010;19(1):229-39. Men in the control group who carried the AA genotype in the paper's coding-strand notation — corresponding to the TT genotype in plus-strand notation — tended toward higher serum DHT levels (P = 0.03). This suggests the minor T allele, or a variant in strong linkage disequilibrium with it, is associated with modestly increased 5-alpha-reductase activity or efficiency, resulting in more testosterone being converted to DHT.

rs7594951 was also among the SRD5A2 tag SNPs examined in a 2014 population-based study by Carmichael et al. investigating sex hormone gene variants in hypospadias — a congenital defect of the male urethra caused by insufficient androgenization during fetal development22 Carmichael et al. investigating sex hormone gene variants in hypospadias — a congenital defect of the male urethra caused by insufficient androgenization during fetal development
Carmichael SL et al. Andrology. 2014;2(1):130-7. The study genotyped 332 tagSNPs across 20 sex hormone metabolism genes in 633 cases and 855 controls born in California. Ten SRD5A2 SNPs showed p < 0.01 in single-SNP analyses; three SRD5A2 haplotype blocks showed odds ratios of 1.4–1.7 for hypospadias. While the paper reports haplotype blocks rather than individual SNP effects for rs7594951, the direction is consistent with DHT availability during genital development influencing hypospadias risk. The effect direction here is opposite to the DHT-level finding: haplotypes conferring lower SRD5A2 function associate with higher hypospadias risk (less DHT during fetal development impairs urethral fusion), while the TT genotype at rs7594951 may associate with higher DHT.

The overall evidence base for rs7594951 as an independent causal variant is limited to these two studies, neither of which reports rs7594951 in isolation with a definitive effect size. The variant should be understood as a possible marker of 5-alpha-reductase activity variation rather than a clinically established risk allele.

Practical Implications

If the minor T allele does increase local DHT production — consistent with the Setlur 2010 findings — CT and TT carriers may experience somewhat stronger androgenic effects in DHT-sensitive tissues over their lifetime. This could manifest as more pronounced androgenetic alopecia in genetically predisposed individuals, a modestly greater tendency toward benign prostatic hyperplasia with age in men, or potentially higher baseline DHT levels on serum hormone testing. The effect magnitude is likely modest given the intronic location and the minor allele frequency of ~10.7%.

For individuals prescribed finasteride (for hair loss or BPH) or dutasteride, intrinsic 5-alpha-reductase activity level at baseline may influence the degree of DHT suppression achieved at standard doses — higher baseline activity could theoretically require different titration. This is speculative at the individual SNP level, as pharmacogenomic data for rs7594951 specifically are not available.

Regarding hypospadias, the developmental window during which DHT levels matter (weeks 8–16 of gestation) is not modifiable postnatally. The hypospadias association is of academic and family planning interest but does not inform actionable intervention in adults.

Interactions

rs7594951 sits in the same gene as the better-characterized V89L variant (rs523349) and the A49T variant (rs9282858). The V89L variant reduces SRD5A2 enzyme activity by approximately 30%, and A49T also alters enzyme kinetics. Haplotypes combining rs7594951 with these coding variants may produce combined effects on DHT output that differ from either variant alone. Literature on the specific haplotype structure involving all three variants is limited, but the SRD5A2 locus should be interpreted as a unit across these SNPs where possible.

The CYP17A1 variant rs743572 influences androgen precursor production upstream of SRD5A2, and variants in the androgen receptor (AR) gene modulate DHT sensitivity in target tissues downstream. Individuals with multiple variants affecting DHT production or response may experience amplified or attenuated androgen-sensitive phenotypes.

Drug Interactions

finasteride altered_response literature
dutasteride altered_response literature

Genotype Interpretations

What each possible genotype means for this variant.

CC Reference Activity Normal

Two copies of the common reference allele; standard SRD5A2 expression and DHT production

You have two copies of the common C allele at this intronic position in SRD5A2. This is the most frequent genotype globally, carried by approximately 80% of people across most ancestry groups. There is no evidence that this genotype alters SRD5A2 expression or DHT production relative to the population average. Your testosterone-to-DHT conversion by the SRD5A2 enzyme is expected to be typical for your background level of enzyme expression.

CT Possible DHT Elevation Intermediate

One copy of the minor T allele; possibly associated with modestly increased DHT production

The association between the T allele and higher serum DHT was identified in the context of a prostate cancer case-control study in Austria (Setlur et al. 2010), where controls with the TT genotype (reported as AA in the study's coding-strand notation) showed elevated DHT (P = 0.03). Heterozygotes were not separately analyzed in that report, so the effect in CT individuals is inferred rather than directly measured.

SRD5A2 tag SNPs in the gene region of rs7594951 were also among 10 variants reaching p < 0.01 in the Carmichael et al. 2014 hypospadias study, which found SRD5A2 haplotype blocks associated with OR 1.4–1.7 for hypospadias risk. The connection to an intrinsic DHT activity effect versus regulatory haplotype effects remains unclear without more detailed functional studies.

TT Elevated DHT Tendency High

Two copies of the minor T allele; the genotype tentatively linked to higher serum DHT levels in published data

The TT homozygote is uncommon enough (estimated ~1% of the population based on a ~10.7% T allele frequency) that it was likely a rare genotype in the original Setlur et al. dataset, possibly represented by very few individuals. The study's P = 0.03 finding for the AA group (TT in plus-strand) may therefore reflect a small-numbers effect.

If the association is real, chronically elevated DHT production throughout life could contribute to: more pronounced androgenetic alopecia in genetically predisposed men and women; increased prostate growth with age in men; and potentially heightened androgenic effects on sebaceous glands and acne. DHT plays a role in fetal external genital virilization, but this developmental window is complete before birth and is not influenced by adult genotype information.

5-alpha-reductase inhibitors like finasteride and dutasteride are specifically designed to suppress DHT by inhibiting SRD5A2. Higher baseline DHT in TT carriers could in principle require attention to treatment adequacy, though prospective pharmacogenomic data for this specific SNP are not available.