rs3788205 — SLC19A1 SLC19A1 intronic variant

Intronic marker in the folate transporter gene; tags SLC19A1 haplotype variation associated with folate-dependent disease risk

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SLC19A1 rs3788205 — A Folate Transporter Haplotype Marker

SLC19A1 (Solute Carrier Family 19 Member 1), also known as the reduced folate carrier (RFC1), is the primary transporter that moves folate and antifolate drugs from the bloodstream into cells. The well-characterized G80A variant rs105126611 rs1051266
The missense SLC19A1 variant most extensively studied for folate transport and methotrexate pharmacogenomics sits in the transmembrane domain and directly affects transporter function. rs3788205 is a separate intronic variant in the same gene — it does not alter the protein itself, but it tags broader genetic variation across the SLC19A1 locus through linkage with adjacent functional variants.

The Mechanism

As an intronic variant, rs3788205 does not directly change the SLC19A1 amino acid sequence. Intronic variants can theoretically influence gene expression through effects on splicing enhancers, regulatory elements, or transcription factor binding sites embedded within introns. However, no functional characterization of this specific site has been published to date. The variant's appearance across multiple folate-pathway disease studies most likely reflects linkage disequilibrium 22 Linkage disequilibrium (LD): nearby variants on the same chromosome are inherited together, so one can be a statistical proxy for another without directly causing any effect with rs1051266 or other functional SLC19A1 variants. The T allele is the minor allele globally (~28% overall, ~30% in Europeans, only ~7% in Africans per dbSNP ALFA data), making it an informative population marker for SLC19A1 haplotype structure.

The Evidence

The clearest direct finding comes from a Phase III lung cancer trial33 Phase III lung cancer trial
Smit EF et al. Biomarker analysis of pemetrexed-carboplatin vs. etoposide-carboplatin in SCLC. Annals of Oncology, 2012, which found that rs3788205 interacted with gamma-glutamyl hydrolase (GGH)-associated SNPs to predict overall survival in patients receiving pemetrexed-carboplatin. This is biologically plausible since pemetrexed, like methotrexate, depends on RFC1/SLC19A1 for cellular entry. An Italian case-control study44 Italian case-control study
Girardi A et al. RFC1 and non-syndromic cleft lip/palate association study in Italy. J Craniomaxillofac Surg, 2014 examined rs3788205 alongside rs1051266 and rs4818789 in the context of cleft lip with or without cleft palate, reporting weak association signals across the three RFC1 polymorphisms. A Japanese autism spectrum disorder study55 Japanese autism spectrum disorder study
Mahmuda NA et al. SLC19A1/RFC1 SNPs in autism spectrum disorder. Int J Mol Sci, 2016 included rs3788205 in a 13-SNP SLC19A1 panel but found no significant association after correction for multiple testing. rs3788205 is not among the five SLC19A1 tagSNPs that reached corrected significance in the colorectal adenoma study Levine AJ et al., 201166 Levine AJ et al., 2011
Cancer Causes Control, folate pathway variation and distal colorectal adenoma.

Taken together, the evidence for this variant as an independent risk factor is weak. The evidence level is emerging — the variant appears across folate-pathway studies but has not been replicated with a clear, directional effect in any single phenotype.

Practical Context

If you carry the minor T allele — particularly as a TT homozygote — your result reflects a less common SLC19A1 haplotype that co-occurs with other folate pathway variants in studies examining anti-folate drug response, birth defects, and gastrointestinal cancer risk. The practical implications are best understood in the context of your other folate pathway results, especially rs1051266 (the G80A missense variant in the same gene) and MTHFR variants.

The most actionable approach for anyone with T-allele status at this locus is to ensure optimal folate intake and to use methylfolate rather than synthetic folic acid — advice consistent with the broader SLC19A1 pathway evidence.

Interactions

rs3788205 is in the same gene as rs1051266 (G80A, His27Arg), the primary functional variant in SLC19A1. Compound haplotypes across these two sites define distinct SLC19A1 genetic backgrounds. Studies of methotrexate toxicity use haplotype-based approaches encompassing both variants alongside rs7499 and rs2838956. If you carry the G80A T allele at rs1051266 in addition to the minor T allele here, you may be on a specific SLC19A1 haplotype associated with altered folate transporter behavior.

Drug Interactions

pemetrexed altered_metabolism literature
methotrexate altered_metabolism literature

Nutrient Interactions

folate altered_metabolism

Genotype Interpretations

What each possible genotype means for this variant.

CC Common Haplotype Normal

Common SLC19A1 haplotype — standard folate transporter background

As the major-allele homozygote, you sit on the most common SLC19A1 haplotype at this locus. The overall clinical picture for your folate transport function depends primarily on rs1051266 (the G80A missense variant in the same gene), not on this intronic marker.

CT Intermediate Haplotype Intermediate

One minor-allele copy — heterozygous SLC19A1 haplotype

The heterozygous state places you on a mixed SLC19A1 haplotype background. Studies examining SLC19A1 variation in cancer risk, birth defects, and antifolate drug response have included rs3788205 as part of haplotype panels. The biological mechanism (if any) is not established for this intronic site specifically. The practical significance depends on your full SLC19A1 haplotype — particularly your rs1051266 genotype.

TT Minor Haplotype Sensitive

Two minor-allele copies — rare SLC19A1 haplotype

The TT genotype is uncommon — particularly rare in individuals of African ancestry (~0.5% TT frequency there) and more common in Europeans (~9%). Studies examining SLC19A1 haplotypes in the context of cancer drug response, congenital defects, and folate metabolism have included this variant. The 2012 lung cancer trial found interactions between rs3788205 and GGH variants for overall survival on pemetrexed-carboplatin. The 2014 Italian cleft palate study found weak association signals across rs3788205 and neighboring RFC1 SNPs.

Because this is intronic and lacks functional characterization, the TT genotype is clinically interpreted as a haplotype marker — its significance depends on the full SLC19A1 genetic context. If you also carry the T allele at rs1051266 (G80A), the combined haplotype picture is more informative than either variant alone.