rs76428106 — FLT3 FLT3 Intronic Splice Variant

FLT3 Splice Variant — When an Immune Regulator Misfires in the Thyroid

The FLT3 gene encodes a receptor tyrosine kinase¹¹ receptor tyrosine kinase
A class of cell-surface receptor proteins that, when activated by their ligand, trigger intracellular signaling cascades controlling cell growth, survival, and differentiation that sits at the top of the immune cell development hierarchy. FLT3 and its ligand (FLT3L) together act as a master controller for the production and mobilization of dendritic cells²² dendritic cells
Specialized immune sentinels that patrol tissues, capture antigens, and present them to T cells to orchestrate adaptive immune responses — the immune system's antigen-presenting specialists. When FLT3 is partially inactivated, the resulting surge in FLT3 ligand floods the body with extra dendritic cells, and in genetically susceptible individuals this excess immune surveillance turns against the thyroid.

rs76428106 is a rare intronic variant in the FLT3 gene that has the largest effect size of any common variant associated with autoimmune thyroid disease. Carrying even one copy of the C allele raises the risk of Hashimoto's thyroiditis and autoimmune hypothyroidism by approximately 46% — a magnitude that rivals clinically actionable pharmacogenomic variants.

The Mechanism

The C allele at rs76428106 generates a cryptic splice site³³ cryptic splice site
An alternative splice signal within an intron that the spliceosome machinery can recognize, redirecting mRNA processing to produce an aberrant transcript within intron 14 of FLT3. In roughly 30% of FLT3 transcripts, this cryptic splice site is used, introducing a premature stop codon⁴⁴ premature stop codon
A UAA/UAG/UGA codon appearing before the normal end of the coding sequence, causing ribosome release and production of a truncated, often non-functional protein that truncates the receptor protein before it encodes the intracellular tyrosine kinase domains⁵⁵ tyrosine kinase domains
The enzymatic domains of FLT3 that phosphorylate downstream signaling proteins; without these, the receptor cannot relay activation signals into the cell. The truncated protein cannot signal, effectively reducing functional FLT3 receptor on hematopoietic precursor cells.

This partial FLT3 inactivation triggers a compensatory homeostatic response: the body ramps up production of FLT3 ligand to drive more signaling through the residual full-length receptors. Each copy of the rs76428106 C allele approximately doubles plasma FLT3L concentration. Elevated FLT3L is a potent stimulus for the expansion of plasmacytoid dendritic cells⁶⁶ plasmacytoid dendritic cells
A specialized subset of dendritic cells that are major producers of type I interferons and can activate autoreactive T and B cells and conventional dendritic cell subsets. This dendritic cell surge increases the probability that thyroid autoantigens are presented to autoreactive T and B cells, breaking peripheral tolerance and initiating the anti-thyroid antibody cascade characteristic of Hashimoto's thyroiditis.

The Evidence

The landmark GWAS by Saevarsdottir et al.⁷⁷ Saevarsdottir et al.
Saevarsdottir S et al. FLT3 stop mutation increases FLT3 ligand level and risk of autoimmune thyroid disease. Nature, 2020 analyzed 30,234 autoimmune thyroid disease cases and 725,172 controls from Iceland and UK Biobank, identifying 99 associated variants at 93 loci. Among all discovered variants, rs76428106-C had the largest effect size: OR = 1.46, p = 2.37 × 10⁻²⁴. The study demonstrated the molecular mechanism directly — the variant was shown to create the cryptic splice site, introduce the stop codon in 30% of transcripts, and double FLT3L plasma levels per allele copy. The C allele frequency of approximately 1.4% in European populations places it in the "low-frequency" category, yet its effect size exceeds most common GWAS risk variants. Beyond thyroid disease, the same C allele was associated with systemic lupus erythematosus (OR = 1.90), rheumatoid arthritis (OR = 1.41), coeliac disease (OR = 1.62), and acute myeloid leukaemia (OR = 1.90), pointing to a broad role for FLT3-mediated immune dysregulation across autoimmune and haematological conditions.

Replication and extension in a larger GWAS: Rand et al. (2025)⁸⁸ Rand et al. (2025)
Rand SA et al. Genome-wide association study and polygenic risk prediction of hypothyroidism. Nature Genetics, 2025 performed a meta-analysis across 113,393 hypothyroidism cases and 1,065,268 controls, identifying 350 associated loci (179 newly reported). The study confirmed that many hypothyroidism risk loci cluster in immune regulatory pathways — specifically blood cell count regulation and the inflammasome — consistent with the FLT3-dendritic cell axis identified in 2020. A polygenic risk score combining genomic variants with anti-TPO antibody levels achieved clinically useful stratification of subclinical hypothyroidism progression risk, supporting the use of anti-TPO antibody testing in carriers of high-risk variants such as rs76428106.

Practical Implications

Because rs76428106-C is rare (approximately 1 in 70 people of European ancestry carry one copy), and because its effect primarily manifests as autoimmune thyroid disease rather than a metabolic defect, the main clinical use is earlier screening for thyroid autoimmunity. Anti-thyroid peroxidase (anti-TPO) antibodies are the earliest detectable marker of thyroid autoimmune activation — they typically appear years before overt hypothyroidism. C allele carriers benefit from knowing that their immune system is primed toward thyroid self-attack, enabling them to monitor for early signs (rising TSH, positive anti-TPO) and begin intervention in the subclinical phase rather than after overt hypothyroidism is established.

The broad autoimmune association profile of this variant (lupus, RA, coeliac) also suggests that rs76428106-C carriers are generally at elevated risk for other autoimmune conditions. Any new symptom involving joint pain, rash, gastrointestinal malabsorption, or unexplained fatigue in a C allele carrier warrants evaluation for co-occurring autoimmune disease.

Interactions

The FLT3 rs76428106 variant operates in the same immune-regulatory space as several established autoimmune risk loci. rs2476601 (PTPN22 R620W) is the most potent common autoimmune risk variant known, affecting B and T cell activation thresholds — individuals carrying both rs2476601-A and rs76428106-C would carry risk signals from both the immune cell production axis (FLT3) and the T cell activation threshold axis (PTPN22). rs2292239 (ERBB3) and rs3184504 (SH2B3) are common autoimmune risk variants that have been associated with thyroid autoimmunity in multiple GWAS. Whether these variants interact supra-additively with rs76428106 has not been directly studied, but their co-occurrence in the same individual would compound overall autoimmune thyroid risk.