Pathogenicity: Frontotemporal Dementia : Benign
Clinical Phenotype: None
Reference Assembly: GRCh37/hg19
Position: Chr17:44073889 A>G
dbSNP ID: rs1052553
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Silent
Codon Change: GCA to GCG
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 9


The human MAPT gene resides within a region of chromosome 17 affected by a large inversion polymorphism of about 900 kb that generates a region of linkage disequilibrium defined by two extended haplotypes, referred to as H1 and H2, or HA and HB (see Pittman et al., 2006 for review). These haplotypes are defined by a series of polymorphisms, including several within the MAPT sequence.  In the case of the synonymous variant that encodes A227A, the minor allele, "G", segregates with the H2 haplotype, whereas the “A” allele is associated with the more common, H1 haplotype. Both alleles have been found in healthy controls as well as patients with various neurodegenerative conditions (Poorkaj et al,. 2001).

The H1 haplotype strongly associates with increased risk of progresssive supranuclear palsy and corticobasal degeneration (e.g., Baker et al., 1999; Houlden et al., 2001; Pittman et al., 2005; Rademakers et al., 2005; Höglinger et al., 2011). The H1 haplotype also has been reported to be associated with risk of late-onset Alzheimer's disease (Myers et al., 2005; Myers et al., 2007; Laws et al., 2007; Abraham et al., 2009). Although this association has not been universally replicated (e.g., Russ et al., 2001; Mukherjee et al., 2007), a comprehensive, large-scale screening study of 9,814 late-onset AD cases and 11,550 controls supported the finding that the less common H2 haplotype is associated with decreased risk of late-onset AD (Allen et al., 2014).

In addition, although both alleles have been found in populations across the world, frequencies are related to ethnicity. The H2 haplotype has a frequency of about 20 percent in Europeans, but is rare in Africans, and almost absent in East Asians (Stefansson et al., 2005). In a large study of genetic variability, the minor allele was found in about 15 percent of those screened, including in people from Asia, Europe, the Middle East, North Africa, and Subsaharan Africa (Guerreiro et al., 2010).



Biological Effect

Unknown. The H2 haplotype has been associated with lower MAPT levels in the cerebellum and temporal cortex of AD subjects (Allen et al., 2104).

Last Updated: 16 Feb 2023


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Paper Citations

  1. . Untangling the tau gene association with neurodegenerative disorders. Hum Mol Genet. 2006 Oct 15;15 Spec No 2:R188-95. PubMed.
  2. . Frequency of tau gene mutations in familial and sporadic cases of non-Alzheimer dementia. Arch Neurol. 2001 Mar;58(3):383-7. PubMed.
  3. . Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum Mol Genet. 1999 Apr;8(4):711-5. PubMed.
  4. . Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype. Neurology. 2001 Jun 26;56(12):1702-6. PubMed.
  5. . Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration. J Med Genet. 2005 Nov;42(11):837-46. PubMed.
  6. . High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy. Hum Mol Genet. 2005 Nov 1;14(21):3281-92. PubMed.
  7. . Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet. 2011 Jul;43(7):699-705. PubMed.
  8. . The H1c haplotype at the MAPT locus is associated with Alzheimer's disease. Hum Mol Genet. 2005 Aug 15;14(16):2399-404. PubMed.
  9. . The MAPT H1c risk haplotype is associated with increased expression of tau and especially of 4 repeat containing transcripts. Neurobiol Dis. 2007 Mar;25(3):561-70. PubMed.
  10. . Fine mapping of the MAPT locus using quantitative trait analysis identifies possible causal variants in Alzheimer's disease. Mol Psychiatry. 2007 May;12(5):510-7. PubMed.
  11. . An association study of common variation at the MAPT locus with late-onset Alzheimer's disease. Am J Med Genet B Neuropsychiatr Genet. 2009 Dec 5;150B(8):1152-5. PubMed.
  12. . The microtubule associated protein Tau gene and Alzheimer's disease--an association study and meta-analysis. Neurosci Lett. 2001 Nov 13;314(1-2):92-6. PubMed.
  13. . Haplotype-based association analysis of the MAPT locus in late onset Alzheimer's disease. BMC Genet. 2007;8:3. PubMed.
  14. . Association of MAPT haplotypes with Alzheimer's disease risk and MAPT brain gene expression levels. Alzheimers Res Ther. 2014;6(4):39. Epub 2014 Jul 1 PubMed.
  15. . A common inversion under selection in Europeans. Nat Genet. 2005 Feb;37(2):129-37. Epub 2005 Jan 16 PubMed.
  16. . A thorough assessment of benign genetic variability in GRN and MAPT. Hum Mutat. 2010 Feb;31(2):E1126-40. PubMed.

Other Citations

  1. Allen et al., 2104

Further Reading


  1. . TAU mutations are not a predominant cause of frontotemporal dementia in Canadian patients. Can J Neurol Sci. 2004 Aug;31(3):363-7. PubMed.
  2. . Frequency of tau mutations in familial and sporadic frontotemporal dementia and other tauopathies. J Neurol. 2004 Sep;251(9):1098-104. PubMed.
  3. . A family study of DRD3 rs6280, SLC1A2 rs3794087 and MAPT rs1052553 variants in essential tremor. Neurol Res. 2016 Oct;38(10):880-7. Epub 2016 Jul 21 PubMed.
  4. . MAPT gene rs1052553 variant is not associated with the risk for multiple sclerosis. Hum Immunol. 2013 Jul 31; PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . High prevalence of mutations in the microtubule-associated protein tau in a population study of frontotemporal dementia in the Netherlands. Am J Hum Genet. 1999 Feb;64(2):414-21. PubMed.


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