rs2471738 — MAPT H1c Sub-haplotype Tag (rs2471738)

MAPT rs2471738 — A Second H1c Tag Confirming Tauopathy Risk

The rs2471738 variant is an intronic SNP in the MAPT gene whose T allele is one of six markers that together define the H1c sub-haplotype — the highest-risk configuration within the broad H1 clade of the MAPT locus. While rs242557 is the most widely studied H1c tagging SNP, rs2471738 was independently analyzed in the same large meta-analysis and yielded nearly identical effect sizes for progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Having two independently validated markers for the same H1c haplotype strengthens confidence in the H1c–tauopathy association and provides a second opportunity for genotyping platforms to capture this risk signal.

The H1c Sub-haplotype Structure

The MAPT locus on chromosome 17q21 is divided into two major clades — H1 and H2 — by an ancient 900-kilobase chromosomal inversion. Within the H1 clade, additional sequence variation defines sub-haplotypes labeled H1a through H1o. The H1c sub-haplotype is characterized by a specific combination of six variants: rs1467967=A, rs242557=A, rs3785883=G, rs2471738=T, del-In9 insertion, and rs7521=G¹¹ The H1c sub-haplotype is characterized by a specific combination of six variants: rs1467967=A, rs242557=A, rs3785883=G, rs2471738=T, del-In9 insertion, and rs7521=G
Together these markers identify a distinct H1 subset with the highest documented risk for 4-repeat tauopathies.

The T allele at rs2471738 is less frequent globally (~18–19% allele frequency) than the A allele at rs242557 (~37% in Europeans). This reflects the nature of haplotype tagging: rs242557 A tags a broader H1c-inclusive group, while rs2471738 T, by requiring more H1c-defining alleles to be present simultaneously, captures the "fully defined" H1c configuration more stringently. An individual carrying rs2471738 T is very likely also carrying rs242557 A, but not necessarily vice versa.

The Mechanism

The H1c haplotype drives elevated tau pathology through transcriptional and post-transcriptional mechanisms. A 2007 study showed that H1c increases both total MAPT expression and the proportion of 4-repeat tau isoforms in human brain tissue²² A 2007 study showed that H1c increases both total MAPT expression and the proportion of 4-repeat tau isoforms in human brain tissue
Four-repeat (4R) tau is the molecular building block of pathological tangles in PSP, CBD, and some Alzheimer's disease subtypes. The rs2471738 T allele, as part of this haplotype, marks the same elevated-expression, 4R-shifted tau biology. Elevated ambient 4R tau lowers the threshold for pathological aggregation when aging, metabolic stress, or injury triggers tau hyperphosphorylation.

The Evidence

A 2017 meta-analysis of 82 case-control studies (Zhang et al., Oncotarget) found the rs2471738 T allele confers an odds ratio of 1.85 (95% CI 1.48–2.31) for PSP — based on 12 independent studies — and OR 2.07 (95% CI 1.32–3.23) for CBD — based on 6 studies³³ A 2017 meta-analysis of 82 case-control studies (Zhang et al., Oncotarget) found the rs2471738 T allele confers an odds ratio of 1.85 (95% CI 1.48–2.31) for PSP — based on 12 independent studies — and OR 2.07 (95% CI 1.32–3.23) for CBD — based on 6 studies
These effect sizes are among the largest for common variants in neurodegenerative disease and replicate across multiple independent cohorts. For Alzheimer's disease, the T allele showed a borderline association (OR 1.04, 95% CI 1.00–1.09), broadly consistent with the modest AD signal seen for other H1c tags.

For comparison, rs242557 A in the same meta-analysis yielded OR 1.96 for PSP and OR 2.51 for CBD — slightly higher effect sizes, reflecting its status as the primary H1c marker with broader coverage. The two SNPs capture overlapping but not fully identical portions of the H1c-carrying population, making them complementary rather than redundant.

A 2015 GWAS of 219 CBD cases confirmed the H1c sub-haplotype as a shared risk factor for CBD and PSP (p = 7.91×10⁻⁶), providing genome-wide level support for the H1c–tauopathy link⁴⁴ A 2015 GWAS of 219 CBD cases confirmed the H1c sub-haplotype as a shared risk factor for CBD and PSP (p = 7.91×10⁻⁶), providing genome-wide level support for the H1c–tauopathy link
This shared genetic architecture aligns with the neuropathological overlap between CBD and PSP, both being 4-repeat tauopathies.

Practical Actions

Like all H1c markers, rs2471738 identifies individuals within the H1 haplotype background who face elevated risk for rare but serious neurodegenerative conditions. PSP affects approximately 6 per 100,000 people, so even a near-doubling of relative risk translates to modest absolute risk — but the signal is biologically real and warrants proactive lifestyle optimization and neurological awareness.

No pharmacological intervention currently targets H1c-specific tau overexpression in healthy individuals. Head trauma prevention, cardiovascular risk factor control, and consistent aerobic exercise represent the primary evidence-based interventions for reducing downstream tauopathy risk.

Interactions

rs2471738 T and rs242557 A are in strong linkage disequilibrium as co-members of the H1c haplotype definition. An individual heterozygous at rs2471738 (CT genotype) is almost certainly also carrying at least one rs242557 A allele. When both are genotyped, they provide a more stringent H1c identification than either alone — only individuals positive for both T and A alleles respectively can be confidently classified as H1c carriers. See rs242557 for the full H1c profile.

The H1c burden compounds with the broader H1/H1 homozygosity captured by rs17649553 and rs1800547. Individuals who are H1/H1 at the broad haplotype level and also carry H1c alleles face the highest tier of tau-related neurodegeneration risk within the MAPT locus. In Alzheimer's disease, the MAPT H1c effect appears most pronounced in APOE ε4 non-carriers, where tau-driven pathology operates more independently of amyloid accumulation.