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=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 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 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.
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.
All Genotypes
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. If you carry the H1 background (TT or CT at rs17649553), the absence of the rs2471738 T allele suggests you are on a non-H1c H1 sub-haplotype with lower PSP/CBD risk than H1c carriers.
One H1c allele at rs2471738 — moderately elevated PSP and CBD risk
You carry one copy of the T allele at rs2471738, one of the six co-defining markers of the MAPT H1c sub-haplotype. Meta-analytic evidence from 12 studies places the per-allele odds ratio for PSP at 1.85 and for CBD at 2.07. As a heterozygote, your risk elevation is intermediate — roughly 1.4-fold above non-carriers for PSP and 1.5-fold for CBD, based on an additive model. About 30% of people globally carry this genotype. PSP and CBD remain rare diseases (PSP affects approximately 6 per 100,000 people), so this relative risk elevation translates to a modest absolute increase. The T allele at rs2471738, acting within the H1c haplotype context, marks elevated 4-repeat tau production that may subtly influence tau biology throughout adult life, even in the absence of overt disease.
Two H1c alleles at rs2471738 — substantially elevated PSP and CBD risk
You carry two copies of the T allele at rs2471738, meaning both of your MAPT loci carry this H1c-defining marker. Meta-analytic data from 12 PSP studies yield OR 1.85 per allele; as a TT homozygote your cumulative risk elevation is substantial — roughly 3.4-fold above CC non-carriers for PSP and 4.3-fold for CBD under an additive model. About 3% of the global population carries this genotype. Critical perspective: PSP affects only approximately 6 per 100,000 people, so a 3-fold relative risk increase translates to an absolute lifetime risk that remains well below 1%. The TT genotype is a meaningful risk modifier but does not determine outcome — it operates within a multifactorial disease landscape shaped by aging, environment, and other genetic factors. Proactive neurological awareness and lifestyle optimization are warranted.