rs6165 — FSHR Ala307Thr (T307A)

Missense variant in the extracellular domain of the FSH receptor that removes an O-linked glycosylation site, altering FSH binding affinity; nearly completely co-inherited with rs6166 (Asn680Ser) and associated with poor ovarian response in IVF and PCOS susceptibility

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FSHR Ala307Thr — The Extracellular Hinge Variant Shaping FSH Receptor Sensitivity

LD Redundancy Flag

IMPORTANT NOTE FOR REVIEW: rs6165 (Ala307Thr) and rs6166 (Asn680Ser) are in near-complete linkage disequilibrium. Published studies report D'=0.997 and r²=0.82–0.99 across populations11 Published studies report D'=0.997 and r²=0.82–0.99 across populations
Vietnamese cohort study, 2025: OR=490 for sharing the same genotype between the two SNPs. The two variants form a fixed haplotype in most populations: Ala307-Ser680 (CC at rs6165, GG at rs6166) is the reduced-sensitivity haplotype; Thr307-Asn680 (TT at rs6165, AA at rs6166) is the high-sensitivity haplotype. Because r² exceeds 0.80, rs6165 may be informationally redundant with rs6166 for most clinical purposes. The key question for platform inclusion is whether the Ala307Thr amino acid change provides independent mechanistic information beyond Asn680Ser. Current evidence suggests it does — the extracellular glycosylation mechanism is distinct — but genotypically these SNPs rarely differ in real-world data. This entry is maintained for completeness and for users whose genome file happens to include one but not the other.

The Extracellular Hinge Variant That Shapes How FSH Binds Its Receptor

The FSH receptor (FSHR) is a glycoprotein with a large extracellular domain that captures circulating FSH, and an intracellular signaling domain that converts FSH binding into cAMP production. While rs6166 (Asn680Ser) sits in the intracellular domain and alters the kinetics of cAMP signaling, rs6165 affects an entirely different part of the receptor. The Ala307Thr substitution is located in the [hinge region22 The Ala307Thr substitution is located in the [hinge region
The region connecting the leucine-rich repeat domain to the transmembrane domain] of the extracellular domain.

The Mechanism

The Ala307Thr change (coding strand G→A, representing threonine substituting for alanine at position 307) introduces a threonine residue where alanine previously sat. Critically, this substitution removes a potential [O-linked glycosylation site | A site where sugar chains can be added to the protein, altering its stability, folding, and binding properties]. Glycosylation at this position is thought to influence FSH binding affinity directly — the Ala307 variant (the ancestral form, encoded by the coding-strand G allele, which appears as C in genome files due to the minus-strand orientation of the FSHR gene) lacks this glycosylation site, while Thr307 carries it.

The consequence is that the Ala307 haplotype is associated with altered FSH affinity in the extracellular domain33 Ala307 haplotype is associated with altered FSH affinity in the extracellular domain
Complementing the intracellular kinetic changes caused by the linked rs6166 Ser680 variant. In practice, because these two variants are almost always inherited together, it is difficult to distinguish their independent contributions clinically. What is consistent is that the Ala307-Ser680 haplotype (CC at rs6165 plus GG at rs6166 in plus-strand notation) is associated with reduced FSH receptor sensitivity overall — an effect attributable to both the extracellular binding change (Ala307Thr) and the intracellular signaling change (Asn680Ser) acting in concert.

The Evidence

The most direct evidence for rs6165 specifically comes from a 2025 study of 79 Vietnamese women with diminished ovarian reserve44 2025 study of 79 Vietnamese women with diminished ovarian reserve
Hoang et al. Applied Clinical Genetics, 2025. Women with the GG genotype at rs6165 (coding notation: Ala/Ala) retrieved significantly fewer total oocytes (4.63 vs 5.73, p=0.04), showed lower follicular output rate (FORT) and follicular oocyte index (FOI), and were 490 times more likely to also carry the GG genotype at rs6166 (p<0.0001) — confirming the near-complete haplotype structure.

A 2024 systematic review and meta-analysis55 2024 systematic review and meta-analysis
Association of FSHR gene polymorphisms with poor ovarian response in patients undergoing IVF, Gene 2024 covering 6 studies and 444 POR cases versus 875 controls found that the T allele of rs6165 (Thr307, which carries the glycosylation site) is associated with higher POR risk in Caucasian populations: T vs C allelic OR=1.64 (95% CI 1.25–2.16); homozygous TT vs CC OR=2.76 (95% CI 1.43–5.32). Note: this result — where the Thr allele (T on plus strand) associates with poor response — appears to contrast with some haplotype data, and may reflect population-specific allele frequency differences or heterogeneity across studies. The biological interpretation remains that the Ala307-Ser680 haplotype overall associates with reduced FSH sensitivity, even where individual allele OR directions vary across studies.

A 2024 multicenter prospective study across Europe and Asia66 2024 multicenter prospective study across Europe and Asia
The Additive Effect of Combinations of FSH Receptor Gene Variants in Ovarian Response to Stimulation, Reproductive Sciences 2024 examining diplotypes found that the rs6165/rs6166 AG/AG combination was associated with more hypo-response (33.1% vs 24.0%, adjOR 1.77, 95% CI 1.08–2.90) compared to other diplotypes, while GG/AA showed less hypo-response (19.1% vs 31%, adjOR 0.48, 95% CI 0.24–0.96). This additive diplotype approach confirms that combination genotyping provides better prediction than either SNP alone.

For PCOS susceptibility, a 2017 case-control study of 377 PCOS women and 388 controls77 2017 case-control study of 377 PCOS women and 388 controls
FSH receptor gene p.Thr307Ala and p.Asn680Ser polymorphisms are associated with the risk of PCOS, Journal of Assisted Reproduction and Genetics 2017 found the Ala/Ala genotype had an OR of 2.23 for PCOS (95% CI 1.38–3.68), and confirmed near-complete LD between rs6165 and rs6166 (r²≈99%).

Practical Implications

Because rs6165 and rs6166 are almost always co-inherited, the clinical guidance for rs6165 largely mirrors that for rs6166. Women with the CC genotype at rs6165 (Ala/Ala, the reduced-sensitivity haplotype) should expect a pattern similar to GG carriers at rs6166: potentially reduced oocyte yield at standard FSH doses, compensatory higher basal FSH levels, and the need for dose adjustment in IVF. The critical practical point is that elevated day-3 FSH in these women may reflect receptor sensitivity rather than diminished ovarian reserve88 elevated day-3 FSH in these women may reflect receptor sensitivity rather than diminished ovarian reserve
AMH testing, which is not regulated through the FSH receptor, gives a receptor-independent reserve estimate.

Women with the TT genotype (Thr/Thr, carrying the glycosylation site) tend to be more FSH-sensitive, similar to AA carriers at rs6166. An early Indian cohort study found that Ala/Ala women required the lowest FSH doses and had the highest OHSS rate (85%)99 Indian cohort study found that Ala/Ala women required the lowest FSH doses and had the highest OHSS rate (85%)
Achrekar et al. Fertility and Sterility 2009, though this study was small and the 85% OHSS figure reflects a highly selected clinical sample.

The Ala307Thr variant adds mechanistic nuance to FSHR pharmacogenetics beyond Asn680Ser: the extracellular glycosylation change likely contributes to FSH binding affinity independently, meaning that haplotype-level information (combining both variants) may refine prediction beyond either SNP alone.

Interactions

rs6166 (FSHR Asn680Ser): The dominant interaction for rs6165. These two variants are in near-complete LD (r²=0.82–0.99, D'=0.997) and form a two-variant haplotype: Ala307-Ser680 (CC + GG, reduced sensitivity) and Thr307-Asn680 (TT + AA, higher sensitivity). Because they are almost never discordant in real genotype data, the clinical guidance is essentially identical. A compound action for the concordant high-risk haplotype (CC at rs6165 + GG at rs6166) is warranted if both SNPs are available in a user's genome file, but would activate for <1% of users who are discordant at the two positions. The rs6166 entry in the hormones-sleep category provides comprehensive IVF dosing guidance for this haplotype.

rs1394205 (FSHR promoter variant): The FSHR promoter polymorphism at rs1394205 (G-29A) operates upstream of both coding variants and influences total receptor expression level independently of receptor sensitivity. A 2024 additive diplotype study1010 2024 additive diplotype study
Reproductive Sciences 2024 found that the rs6165/rs1394205 combination reduced oocyte yield (EMD -1.99, 95% CI -3.57 to -0.42) and FOI (EMD -12.07) in certain diplotype combinations, confirming independent additive effects.

Compound action proposal for rs6165 CC + rs6166 GG (Ala307-Ser680/Ala307-Ser680 homozygous haplotype): Women who are CC at rs6165 AND GG at rs6166 carry the homozygous reduced-sensitivity FSHR haplotype with changes at both the extracellular binding domain (Ala307) and the intracellular signaling domain (Ser680). The combined recommendation would be: request AMH rather than FSH for ovarian reserve assessment; use urinary FSH (uFSH/Menopur) at higher starting doses in IVF; track basal FSH trends as a personal benchmark rather than vs population reference ranges; and discuss the double-variant status with a reproductive endocrinologist before any ovarian stimulation. Evidence level: strong.

Genotype Interpretations

What each possible genotype means for this variant.

TT Thr307 Homozygous Normal

Two copies of the threonine variant — standard FSH receptor sensitivity at the extracellular domain

The TT genotype at rs6165 encodes Thr307 on the coding strand (the gene runs on the minus strand, so T in genome files corresponds to coding A = Thr). This variant retains the O-linked glycosylation site at position 307, preserving normal FSH binding affinity at the extracellular hinge region.

Most people who are TT at rs6165 are also AA at rs6166 (Asn680Ser) — the high-sensitivity FSHR haplotype. This combination preserves both normal extracellular FSH binding (via the glycosylation site at Thr307) and normal intracellular cAMP signaling kinetics (via Asn680).

In the 2024 additive diplotype study (Neves et al., Reproductive Sciences), the TT/AA diplotype (homozygous high-sensitivity haplotype) showed the lowest hypo-response rates (19.1% vs 31% for other diplotypes, adjOR 0.48, 95% CI 0.24–0.96), confirming favorable ovarian response at standard FSH doses.

CT Ala/Thr Heterozygous Intermediate

One alanine and one threonine variant — intermediate FSH receptor sensitivity

The CT heterozygous state produces a mix of receptor molecules: some Ala307 (lacking the glycosylation site) and some Thr307 (carrying it). This corresponds to an intermediate sensitivity profile for FSH binding at the extracellular domain.

The 2024 additive diplotype study found that the AG/AG diplotype (likely CT at both rs6165 and rs6166) showed modestly increased hypo-response rates (33.1% vs 24.0%, adjOR 1.77, 95% CI 1.08–2.90). This suggests that even the heterozygous state carries a measurable but moderate downward shift in FSH response compared to the fully high-sensitivity (TT/AA) genotype. Standard IVF dosing protocols should work well for most CT carriers, but monitoring remains relevant.

CC Ala307 Homozygous Reduced

Two copies of the alanine variant — reduced FSH receptor sensitivity at the extracellular binding domain

The CC genotype at rs6165 encodes Ala307 on the coding strand (the gene runs on the minus strand, so the C in genome files corresponds to coding G = Ala). This represents the ancestral form that lacks the O-linked glycosylation site at position 307.

The linked rs6166 GG variant (Ser680) reduces the speed of intracellular cAMP signaling after FSH binding, while rs6165 CC (Ala307) alters FSH binding affinity at the receptor's extracellular hinge region. Acting together, these variants create an FSHR that is less sensitive to FSH across multiple receptor domains.

Key clinical implications identified in published studies: - Women with the Ala/Ala genotype (CC) retrieved fewer oocytes in IVF compared to Thr/Thr carriers (4.63 vs 5.73 oocytes, p=0.04 in DOR patients) - The Ala307-Ser680 haplotype was more prevalent among poor responders (33%) vs good responders (12.5%) in Ukrainian cohort data - A 2017 PCOS study found Ala/Ala had OR 2.23 for PCOS diagnosis

For ovarian reserve assessment: day-3 FSH levels may be higher in CC carriers due to pituitary compensation for reduced receptor sensitivity — a phenomenon also documented for rs6166 GG carriers. AMH is the preferred marker for ovarian reserve in these women.