rs2471738 — MAPT H1c Sub-haplotype Tag (rs2471738)

Intronic MAPT variant whose T allele co-defines the H1c sub-haplotype, independently conferring OR 1.85 for progressive supranuclear palsy and OR 2.07 for corticobasal degeneration in the same meta-analysis validating rs242557

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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). 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. 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).

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)44 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)
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

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.

Genotype Interpretations

What each possible genotype means for this variant.

CC No H1c Alleles Normal

No rs2471738 risk alleles — baseline PSP and CBD risk at this marker

You carry two copies of the C allele at rs2471738, meaning this particular marker does not identify H1c sub-haplotype carrying. Your risk for progressive supranuclear palsy and corticobasal degeneration at this locus is at baseline. Approximately 66% of people globally share this genotype.

This result is most informative together with rs242557: if you also carry GG at rs242557, you are highly unlikely to carry the H1c sub-haplotype.

CT H1c Heterozygote Intermediate

One H1c allele at rs2471738 — moderately elevated PSP and CBD risk

rs2471738 T is one of the six alleles that together define the H1c haplotype. Your single-copy status provides intermediate risk elevation between the CC (lowest) and TT (highest) genotypes.

TT H1c Homozygote High Risk

Two H1c alleles at rs2471738 — substantially elevated PSP and CBD risk

TT homozygosity at rs2471738 places you at the highest end of the H1c risk spectrum captured by this marker.

For Alzheimer's disease, the T allele shows only borderline association (OR 1.04), so the primary clinical relevance of this TT genotype is concentrated in PSP and CBD risk.