rs2153157 — SYCP2L SYCP2L splice-efficiency variant

Intronic SYCP2L variant in a U12-type minor intron; the A allele splices more efficiently in oocytes, raising SYCP2L expression and supporting primordial follicle survival — the G allele reduces expression and associates with lower anti-Müllerian hormone levels and earlier natural menopause

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SYCP2L rs2153157 — The Splice Switch That Calibrates Your Ovarian Clock

Inside the nucleus of every primordial follicle oocyte, a molecular scaffold called the synaptonemal complex zips homologous chromosomes together and guides the recombination that generates genetic diversity. SYCP2L — synaptonemal complex protein 2-like — is the centromere anchor of that scaffold, expressed exclusively in oocytes and essential for primordial follicle survival. The rs2153157 variant determines how efficiently a critical intron in the SYCP2L gene is spliced, calibrating how much functional protein your oocytes can produce across your reproductive lifetime.

The Mechanism

rs2153157 sits within intron 4 of SYCP2L, inside a U12-type minor intron11 U12-type minor intron
a rare class of introns processed by the minor spliceosome, comprising less than 0.5% of all human introns; characterised by AT-AC terminal dinucleotides rather than the canonical GT-AG. The variant changes a single nucleotide at a position critical for minor spliceosome recognition. The A allele is spliced significantly more efficiently than the G allele in mouse oocytes, generating more complete SYCP2L transcript. The G allele reduces splicing efficiency, lowering the steady-state level of SYCP2L mRNA — and therefore the amount of protein available to stabilise oocyte centromeres during meiotic prophase I.

The consequence of insufficient SYCP2L was demonstrated in knockout mice: female animals lacking the protein undergo a significantly accelerated loss of primordial oocytes with age22 significantly accelerated loss of primordial oocytes with age
the reserve of immature oocytes laid down before birth; once depleted, they cannot be replaced, and become subfertile earlier than wild-type controls. At the clinical extreme, complete loss-of-function mutations in SYCP2L cause premature ovarian insufficiency (POI) in humans, with secondary amenorrhoea, undetectable AMH, and elevated FSH before age 40.

The Evidence

The 6p24.2/SYCP2L locus was first associated with age at natural menopause in a 2009 GWAS of 17,438 women (PMID 19448621), where rs2153157 emerged as a lead variant. The association was subsequently confirmed in the landmark Ruth et al. 2021 meta-analysis33 Ruth et al. 2021 meta-analysis
Genetic insights into biological mechanisms governing human ovarian ageing. Nature 596:393 of 201,323 women — one of the best-powered studies of ovarian aging genetics ever conducted. The SYCP2L locus ranks among the strongest single-gene effects on menopause timing in that study.

Functional validation came from Zhou et al. 201544 Zhou et al. 2015
Accelerated reproductive aging in females lacking a novel centromere protein SYCP2L. Hum Mol Genet 24:6505–6514, who demonstrated the mechanistic link: the A allele of rs2153157 splices its U12-type intron more efficiently in oocytes, explaining at a molecular level why the A allele associates with later menopause in GWAS data.

Clinically, Rosa et al. 202355 Rosa et al. 2023
Involvement of SYCP2L and TDRD3 gene variants on ovarian reserve and reproductive outcomes. JBRA Assist Reprod 27:428–435 found that women carrying the AA genotype at rs2153157 had significantly lower AMH levels (2.9 ng/mL) compared to heterozygous GA carriers (3.7 ng/mL; p=0.01) in a cross-sectional study of 149 IVF patients. In a larger IVF cohort of 471 cycles, Laisk-Podar et al. 201566 Laisk-Podar et al. 2015 found this variant associated with the amount of rFSH required per oocyte retrieved (p=0.049) and with biochemical and clinical pregnancy rates (p=0.024 and 0.011).

Practical Actions

Because rs2153157 acts through SYCP2L expression in oocytes, monitoring anti-Müllerian hormone (AMH) provides a direct window into whether the variant's predicted effect on reserve is materialising. AMH is secreted by growing follicles and is the most sensitive early marker of declining reserve — detectable reductions occur years before any change in menstrual cycle regularity or FSH levels.

For GG carriers, a proactive AMH baseline before age 33 allows time to act on a declining trajectory. Coenzyme Q10 in the ubiquinol form has the strongest evidence base for supporting mitochondrial function in aging oocytes, where ATP availability intersects with the chromosome-pairing process that SYCP2L governs.

Interactions

rs2153157 and rs9348724 are two independent signals at the same SYCP2L locus on chromosome 6p24.2. rs9348724 is a regulatory variant ~2 kb upstream of the gene, while rs2153157 is the intronic splice-efficiency variant. They are not in complete linkage disequilibrium — a carrier of the unfavourable allele at one position may or may not carry it at the other. Women who carry the risk allele at both positions may have more severely impaired SYCP2L expression, with a compound effect on oocyte survival and menopause timing.

Genotype Interpretations

What each possible genotype means for this variant.

AA Efficient Splice / Later Menopause Beneficial

Two copies of the efficient A allele — highest SYCP2L expression and later menopause trajectory

The AA genotype means both copies of intron 4 in the SYCP2L gene are processed by the minor spliceosome with higher efficiency, generating more functional SYCP2L mRNA per oocyte. This increased protein dosage helps maintain centromere integrity during the prolonged meiotic arrest of primordial follicles — potentially preserving the quality and quantity of the follicular reserve over a longer period.

The Rosa 2023 IVF study (n=149) found that the AA genotype group had lower mean AMH than GA carriers in that specific clinical sample; this may reflect selection bias in an IVF population rather than a causal downward shift, and is in the opposite direction to the large GWAS evidence showing A = later menopause. The population-level GWAS signal (n > 200,000) is the stronger basis for interpreting the A allele as protective.

AG Intermediate Splice Efficiency Intermediate

One A allele, one G allele — intermediate SYCP2L expression

In the Rosa 2023 IVF cohort (n=149), heterozygous GA women had the highest median AMH levels (3.7 ng/mL) — numerically higher than both GG (not observed in that sample) and AA (2.9 ng/mL, p=0.01 vs GA). One possible explanation is that balanced heterozygosity at this locus provides an intermediate transcript level that is optimal in the context of IVF patients selected for a specific range of reserve. Across larger GWAS populations, the additive model predicts intermediate menopause timing for heterozygotes.

Because the Rosa 2023 sample had no GG individuals, the full genotype range across this variant was not captured, which limits interpretation of the within-IVF-cohort AMH pattern. The GWAS data from hundreds of thousands of women is the primary basis for directional effect; monitoring AMH and antral follicle count provides the most informative personal data point.

GG Reduced Splice Efficiency / Earlier Menopause Risk Decreased

Two copies of the G allele — reduced SYCP2L splice efficiency and earlier menopause trajectory

Functional experiments in mouse oocytes showed that the G allele of rs2153157 is spliced less efficiently than the A allele, resulting in a lower steady-state level of SYCP2L mRNA. SYCP2L protein localises to oocyte centromeres during meiotic arrest and is required to prevent progressive primordial follicle loss: mice lacking the protein lose their oocyte reserve faster and become subfertile earlier. Homozygous loss-of-function mutations in SYCP2L cause premature ovarian insufficiency in humans (OMIM 620840).

The GWAS data from over 200,000 women consistently shows the G allele as the menopause- advancing allele. Clinical data from IVF cohorts (Laisk-Podar 2015, n=471 cycles) links variants at this locus to FSH dose requirements and pregnancy rates. Monitoring AMH provides the most direct individual assessment of whether this genetic signal is translating into measurable reserve reduction.