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 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 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 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 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-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 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 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 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%)
| 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 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.
All Genotypes
Two copies of the threonine variant — standard FSH receptor sensitivity at the extracellular domain
You carry two copies of the Thr307 variant at rs6165 (TT in genome-file notation, coding A/A). This is the genotype that carries the O-linked glycosylation site at position 307, and is associated with normal-to-high FSH receptor sensitivity at the extracellular domain. About 27% of the general population globally shares this genotype, with higher frequencies in East Asian populations (~42%) and lower in African populations (~8%). In the context of IVF, TT carriers are in the same functional group as AA carriers at rs6166 (Asn680Ser) — the high-sensitivity FSHR haplotype. Standard ovarian stimulation protocols should work well, though individual response depends on many factors beyond genotype.
One alanine and one threonine variant — intermediate FSH receptor sensitivity
You carry one copy each of the Ala307 (C, coding G) and Thr307 (T, coding A) alleles at rs6165. This is the most common genotype globally and in most populations (approximately 50% frequency). Your FSH receptor profile is intermediate between the two homozygous groups, with one receptor allele carrying the glycosylation site (Thr307) and one without (Ala307). Most people who are CT at rs6165 are also AG at rs6166 (Asn680Ser) — the heterozygous state for the linked variant. In IVF studies, the AG/AG diplotype (heterozygous at both positions) is associated with modestly higher hypo-response risk (OR 1.77) compared to other diplotype combinations, though individual variation is substantial.
Two copies of the alanine variant — reduced FSH receptor sensitivity at the extracellular binding domain
You carry two copies of the Ala307 variant at rs6165 (CC genotype in genome-file notation), which places you in the reduced-sensitivity FSHR haplotype. This variant removes an O-linked glycosylation site from the extracellular domain of the FSH receptor, altering FSH binding affinity. About 23% of the general population shares this genotype globally, though frequencies differ by ancestry (higher in African populations at ~50%, lower in East Asian populations at ~12%). In practical terms, this genotype is almost always paired with the GG genotype at rs6166 (Asn680Ser) — together forming the Ala307-Ser680 haplotype associated with reduced ovarian FSH response. Women with this genotype may produce fewer oocytes at standard FSH doses and may have higher basal FSH levels that can mimic diminished ovarian reserve on a standard day-3 panel.