Mutations

Search Mutations

Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.

Search Results

MAPT (107)

MAPT encodes the microtubule associated protein tau, a protein central to Alzheimer’s disease neuropathology. MAPT mutations are not linked to familial forms of AD, but can cause frontotemporal dementia (FTD) and several other tauopathies. The pathogenic mutations, which can be either exonic or intronic, generally alter the relative production of tau isoforms and lead to changes in microtubule assembly and/or the propensity of tau to aggregate.

Mutation Clinical
Phenotype
Pathogenicity Neuropathology Biological Effect Genomic Position Genomic Region Mutation Type
Codon Change
Research
Models
Primary
Papers
P4T
None AD : Not Pathogenic Not applicable. Unknown; predicted probably damaging in silico.

Coding
Exon 1
Point, Missense
CCC to ACC
0 Sala Frigerio et al., 2015
R5C
Parkinson's Disease Dementia PDD : Unclear Pathogenicity Unknown. Unknown.

Coding
Exon 1
Point, Missense
CGC to TGC
0 Schulte et al., 2015
R5H
Frontotemporal Dementia FTD : Unclear Pathogenicity, AD : Unclear Pathogenicity Neuronal loss in the frontal and temporal lobes; Tau deposits predominantly in glia, progressive supranuclear palsy-like straight tubules; Accumulation of 4-repeat (4R), Sarkosyl-insoluble tau.   Reduces tau's ability to promote microtubule assembly; Increases fibril formation in vitro.

rs63750959
Coding
Exon 1
Point, Missense
CGC to CAC
0 Hayashi et al., 2002
R5L
Progressive Supranuclear Palsy Other Tauopathy : Pathogenic Aggregated insoluble tau in subcortical regions was predominantly 4-repeat (4R) tau with 0 or 1 amino terminal inserts (i.e. 0N4R or 1N4R). Insoluble tau in cortical regions also contained 1N3R tau. Reduces tau's ability to promote microtubule assembly; No effect on the ratio of tau isoforms synthesized.

rs63750959
Coding
Exon 1
Point, Missense
CGC to CTC
0 Poorkaj et al., 2002
H14H
None FTD : Not Pathogenic Not applicable. Unknown.

Coding
Exon 1
Point, Silent
CAC to CAT
0 Guerreiro et al., 2010
T17M
None FTD : Not Pathogenic Not applicable. In silico analysis predicted a possible effect on protein function.

rs144611688
Coding
Exon 1
Point, Missense
ACG to ATG
0 Guerreiro et al., 2010
Y18Y
None FTD : Not Pathogenic Not applicable. Unknown.

rs63750811
Coding
Exon 1
Point, Silent
TAC to TAT
0 Houlden et al., 1999;
Guerreiro et al., 2010
T30A
None FTD : Not Pathogenic Not applicable. Unknown.

Coding
Exon 1
Point, Missense
ACC to GCC
0 Guerreiro et al., 2010
T39T
None FTD : Unclear Pathogenicity Unknown. Unknown.

rs63750529
Coding
Exon 1
Point, Silent
ACG to ACA
0 Houlden et al., 1999
A41T
Parkinson's Disease PD : Unclear Pathogenicity Unknown. Unknown.

rs115239819
Coding
Exon 1
Point, Missense
GCT to ACT
0 Schulte et al., 2015
G55R
Frontotemporal Dementia FTD : Pathogenic Unknown; frontal and temporal atrophy by MRI. In vitro 4-repeat (4R) tau with the G55R mutation nucleates microtubule assembly more effectively than wild-type 4R tau. This effect appears to be isoform-specific, and was not seen in 3R tau.

Coding
Exon 2
Point, Missense
GGA to AGA
0 Iyer et al., 2013
V75A
Frontotemporal Dementia FTD : Unclear Pathogenicity Frontotemporal atrophy and fronto-mesial and parietal left hypoperfusion. Unknown.

Coding
Exon 3
Point, Missense
GTG to GCG
0 Gallo et al., 2010
G86S
None FTD : Unclear Pathogenicity Frontal hypometabolism by PET. No effect on normal splicing of exons 2 or 3; Creation of a predicted phosphorylation site and a predicted O-glycosylation site.

rs63751135
Coding
Exon 3
Point, Missense
GGC to AGC
0 Stanford et al., 2004
A90V
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown; predicted benign in silico.

Coding
Exon 3
Point, Missense
GCC to GTC
0 Sala Frigerio et al., 2015
A152T
Alzheimer's Disease, Dementia with Lewy Bodies, Frontotemporal Dementia, Corticobasal Degeneration, Progressive Supranuclear Palsy, pallido-nigro-luysial atrophy variant of progressive supranuclear palsy, Other Tauopathy, Parkinson's Disease Dementia AD : Risk Modifier, FTD : Risk Modifier, DLB : Risk Modifier Extremely variable: Typically prominent tau pathology with variable involvement of Lewy bodies, amyloid plaques, or TDP-43 pathology. Reduced ability to bind microtubules; Less efficient microtubule assembly and impaired microtubule stability; More prone to tau oligomer formation and proteolysis by caspases.

rs143624519
Coding
Exon 7
Point, Missense
GCC to ACC
2 Kovacs et al., 2010;
Coppola et al., 2012
P176P
None FTD : Not Pathogenic Not applicable. Unknown.

rs1052551
Coding
Exon 7
Point, Silent
CCG to CCA
0 Rizzu et al., 1999
A178T
None FTD : Not Pathogenic Not applicable. Unknown.

rs63750612
Coding
Exon 7
Point, Missense
GCT to ACT
0 Houlden et al., 1999
G200E
None FTD : Not Pathogenic Not applicable. Unknown; predicted possibly damaging in silico.

Coding
Point, Missense
0 Sassi et al., 2014
P200P
None FTD : Not Pathogenic Not applicable. Unknown.

Coding
Exon 9
Point, Silent
CCC to CCT
0 Guerreiro et al., 2010
P202L
None FTD : Not Pathogenic Not applicable. Unknown.

rs63750417
Coding
Exon 4a
Point, Missense
CCG to CTG
0 Lilius et al., 1999
R211H
None FTD : Not Pathogenic Unknown. Unknown.

Coding
Point, Missense
CGC to CAC
0 Schulte et al., 2015
G213R
Alzheimer's Disease FTD : Not Pathogenic, AD : Unclear Pathogenicity Unknown. Unknown; predicted possibly damaging in silico.

rs76375268
Coding
Exon 4a
Point, Missense
GGG to AGG
0 Jin et al., 2012
V224G
Alzheimer's Disease, None FTD : Not Pathogenic, AD : Unclear Pathogenicity Unknown. Unknown; predicted possibly damaging in silico.

rs141120474
Coding
Exon 4a
Point, Missense
GTC to GGC
0 Jin et al., 2012
A227A
None FTD : Not Pathogenic Not applicable. Unknown. This variant segregates with the H2 haplotype, which may be associated with decreased tau levels in the brain.

rs1052553
Coding
Exon 9
Point, Silent
GCA to GCG
0 Rizzu et al., 1999
Q230R
Alzheimer's Disease, None FTD : Not Pathogenic, AD : Unclear Pathogenicity Not applicable. Unknown.

rs63750072
Coding
Exon 4a
Point, Missense
CAA to CGA
0 Rademakers et al., 2004
A239T
Frontotemporal Dementia FTD : Not Pathogenic Found in an individual with tau-negative microvacuolar-type neuropathology attributed to a GRN mutation. Unknown.

rs63750096
Coding
Exon 9
Point, Missense
GCC to ACC
0 Pickering-Brown et al., 2002
N255N
None FTD : Not Pathogenic Not applicable. Unknown.

rs17652121
Coding
Exon 9
Point, Silent
AAT to AAC
0 Poorkaj et al., 1998
K257T
Tauopathy consistent with Pick's Disease Other Tauopathy : Pathogenic, FTD : Unclear Pathogenicity Frontotemporal atrophy, especially in the temporal lobes. Numerous tau-positive Pick bodies in the neocortex, hippocampus, and some subcortical regions, which resembled those of sporadic Pick's disease. Diffuse hyperphosphorylated tau in some cell bodies. Recombinant tau protein with the K257T mutation showed reduced ability to promote microtubule assembly.

rs63750129
Coding
Exon 9
Point, Missense
AAG to ACG
0 Rizzini et al., 2000;
Pickering-Brown et al., 2000
I260V
Frontotemporal Dementia FTD : Pathogenic Extensive tau pathology, but no neurofibrillary tangles or Pick bodies. Mild macroscopic atrophy of the frontal lobes and dilatation of the anterior lateral ventricles, bilateral subdural hematomas. Neurodegeneration with gliosis, mild microvacuolation, and neuronal atrophy and loss in the frontal lobes. Selective increase in tau aggregation (four-repeat isoforms only); No disruption of exon 10 splicing.

rs63751249
Coding
Exon 9
Point, Missense
ATC to GTC
0 Grover et al., 2003
L266L
None FTD : Not Pathogenic Not applicable. Unknown.

Coding
Exon 9
Point, Silent
CTG to CTA
0 Guerreiro et al., 2010
L266V
Frontotemporal Dementia FTD : Pathogenic Severe atrophy of the frontal and temporal lobes; Extensive neuronal loss and gliosis; Many tau-positive inclusions, including Pick bodies; Tau-positive argyrophilic astrocytes with stout filaments and round or irregular argyrophilic inclusions. Increased levels of exon 10+ tau mRNA and soluble four-repeat (4R) tau; Decreased rate and extent of tau-induced microtubule assembly; A 3R isoform-specific increase in tau self-assembly.

rs63750349
Coding
Exon 9
Point, Missense
CTG to GTG
1 Kobayashi et al., 2003;
Hogg et al., 2003
P270P
None FTD : Not Pathogenic Not applicable. Unknown.

rs11568305
Coding
Exon 9
Point, Silent
CCG to CCA
0 Rizzu et al., 1999
G272V
Frontotemporal Dementia, Tauopathy consistent with Pick's Disease FTD : Pathogenic Severe frontotemporal lobe atrophy; Neuronal loss in hippocampus and caudate nucleus; "Ballooned cells" in cortex and basal ganglia; Tau-positive inclusions in multiple cortical and subcortical areas. Mutant tau proteins are more favorable substrates for phosphorylation than wild-type tau.

rs63750376
Coding
Exon 9
Point, Missense
GGC to GTC
2 Hutton et al., 1998
G273R
Frontotemporal Dementia FTD : Pathogenic Unknown. Unknown.

Coding
Exon 9
Point, Missense
GGG to AGG
0 van der Zee et al., 2006
N279K
Frontotemporal Dementia FTD : Pathogenic Widespread neuronal and glial tau accumulation in the cortex, basal ganglia, brain-stem nuclei, and white matter. Insoluble fraction is primarily 4R tau. Prominent tau deposition in the medial temporal cortices and upper and lower motor neurons with corticospinal tract degeneration. Affects splicing similar to many of the intronic mutations, resulting in more frequent inclusion of exon 10 in mRNA transcripts.

rs63750756
Coding
Exon 10
Point, Missense
AAT to AAG
0 Wszolek et al., 1992
K280del
Alzheimer's Disease, Frontotemporal Dementia, None, Tauopathy consistent with Pick's Disease FTD : Unclear Pathogenicity, AD : Unclear Pathogenicity Variable: Pick bodies comprised of 3R but not 4R tau and severe atrophy of the frontal and temporal cortices. Alternatively, tangles (Braak stage IV), neuritic amyloid plaques, extensive Lewy body pathology, moderate to severe atherosclerosis in brain vessles, and mild amyloid angiopathy.   The K280del variant is unusal in that it inhibits exon 10 inclusion and leads to an excess of 3-repeat (3R) tau transcripts. It also has been shown to reduce tau's ability to promote microtubule assembly.

rs63750688
Coding
Exon 10
Deletion
AAG to ---
2 Momeni et al., 2009;
Rizzu et al., 1999
L284L
Frontotemporal Dementia FTD : Pathogenic A variety of tau aggregates in both neurons and glia. In addition, a substantial number of diffuse and neuritic Aβ plaques, possibly due to coincident AD. The silent L284L increases transcripts containing exon 10 and decreases transcripts lacking exon 10. The mutation is thought to destroy an exon-splicing silencing element.

rs63751423
Coding
Exon 10
Point, Silent
CTT to CTC
0 D'Souza et al., 1999
L284R
Progressive Supranuclear Palsy Other Tauopathy : Pathogenic, FTD : Not Pathogenic Unknown. Unknown.

Coding
Exon 10
Point, Missense
CTT to CGT
0 Rohrer et al., 2011
D285D
None FTD : Not Pathogenic Not applicable. Unknown.

rs63750222
Coding
Exon 4a
Point, Silent
GAC to GAT
0 Poorkaj et al., 1998
D285N
Progressive Supranuclear Palsy, None FTD : Not Pathogenic, Other Tauopathy : Incomplete Penetrance Unknown. Unknown.

rs62063786
Coding
Exon 4a
Point, Missense
GAC to AAC
0 Poorkaj et al., 1998;
Higgins et al., 1999
S285R
Progressive Supranuclear Palsy FTD : Unclear Pathogenicity, PSP : Pathogenic Unknown. In vitro, this mutation affects exon 10 splicing, resulting in the overproduction of tau isoforms containing four microtubule binding repeat domains (4R tau).

Coding
Exon 10
Point, Missense
AGC to AGA
0 Ogaki et al., 2012
V287I
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown.

149280278
Coding
Exon 10
Point, Missense
GTC to ATC
0 Jin et al., 2012
V289A
None FTD : Not Pathogenic Not applicable. Unknown.

rs62063787
Coding
Exon 4a
Point, Missense
GTA to GCA
0 Poorkaj et al., 1998
C291R
Apraxia of Speech, Corticobasal Syndrome Corticobasal Syndrome : Unclear Pathogenicity Unknown; MRI showed global atrophy of the cerebrum, especially in the left posterior frontal lobe. Unknown. In silico analysis predicted an increase in exon 10 splicing.

Coding
Exon 10
Point, Missense
TGT to CGT
0 Marshall et al., 2015
N296del
(ΔN296)
Progressive Supranuclear Palsy, Parkinson's Disease Other Tauopathy : Pathogenic Atrophy of the right precentral gyrus and the brainstem, as well as neuron loss and gliosis in the substantia nigra, several brainstem nuclei, and diencephalon. Hyperphosphorylated tau and neurofibrillary tangles in neurons in many brain regions. Accumulated tau in astrocytes and oligodendrocytes. The N296del mutation has little or no effect on exon 10 splicing, but substantially reduces tau's ability to promote microtubule assembly and increases its aggregation into filaments.

rs63751392
Coding
Exon 10
Deletion
AAT to ---
0 Pastor et al., 2001
N296D
Frontotemporal Dementia FTD : Pathogenic Unknown; imaging showed temporal atrophy. Unknown.

Coding
Exon 10
Point, Missense
AAT to GAT
0 Cohn-Hokke et al., 2014
N296H
Frontotemporal Dementia FTD : Pathogenic Localized frontotemporal lobe atrophy; A proliferation of tau-positive astrocytes; An accumulation of phosphorylated tau in both neurons and glia; An accumulation of four-repeat (4R) tau. This mutation increases the inclusion of exon 10 in tau mRNA and therefore increases the ratio of 4R/3R tau. It reduces tau's ability to promote tubulin polymerization and microtubule assembly. It has little to no effect on tau filament formation.

rs63750416
Coding
Exon 10
Point, Missense
AAT to CAT
0 Iseki et al., 2001
N296N
Frontotemporal Dementia, Progressive Supranuclear Palsy FTD : Pathogenic, PSP : Pathogenic Frontotemporal atrophy; Neuronal loss in the globus pallidus, substantia nigra, and locus ceruleus; Swollen achromatic neurons and tau-positive inclusions throughout the brain; Plaques and tangles were rare in the hippocampus and cerebral cortex. Increased inclusion of exon 10 in tau mRNA and thus increased the ratio of 4R/3R tau protein.

rs63750912
Coding
Exon 10
Point, Silent
AAT to AAC
0 Spillantini et al., 2000
A297V
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown.

Coding
Exon 4a
Point, Missense
GCC to GTC
0 Jin et al., 2012
V300I
None FTD : Not Pathogenic Not applicable. Unknown; predicted benign and well-tolerated in silico.

Coding
Exon 10
Point, Missense
GTC to ATC
0 Guerreiro et al., 2010
P301L
Frontotemporal Dementia FTD : Pathogenic Tau aggregates consisting mainly of 4-repeat (4R) isoforms. Numerous intracytoplasmic tau deposits in neurons and glia in multiple brain regions, including the hippocampus, neocortex, and substantia nigra. Severe neuronal loss, gliosis, and a few ballooned cells in the frontal and temporal cortices. Strongly promotes β-sheet formation and accelerates the formation of paired helical filament; Does not affect exon 10 splicing.

rs63751273
Coding
Exon 10
Point, Missense
CCG to CTG
8 Hutton et al., 1998;
Dumanchin et al., 1998;
Clark et al., 1998;
Spillantini et al., 1998
P301P
Frontotemporal Dementia FTD : Not Pathogenic Patient had severe neuronal loss in the frontal and temporal cortices, globus pallidus, substantia nigra, red nucleus, and dentate nucleus. Tau-positive fibrillar structures in neurons and glia in these regions. The pathology was attributed to the IVS10+11 mutation in MAPT, which the patient also carried. No change in the ratio of 3-repeat (3R) to 4-repeat (4R) tau isoforms.

rs63751395
Coding
Exon 10
Point, Silent
CCG to CCA
0 Miyamoto et al., 2001
P301S
Frontotemporal Dementia FTD : Pathogenic Frontotemporal atrophy and extensive inclusions of hyperphosphorylated tau in neurons and glia. Recombinant tau protein with the P301S mutation showed a greatly impaired ability to promote microtubule assembly.

rs63751438
Coding
Exon 10
Point, Missense
CCG to TCG
3 Bugiani et al., 1999;
Sperfeld et al., 1999;
Lossos et al., 2003
P301T
Frontotemporal Dementia FTD : Pathogenic Mild global atrophy that was more prominent in the frontal and temporal lobes. Unknown.

rs63751438
Coding
Exon 10
Point, Missense
CCG to ACG
0 Lladó et al., 2007
G303V
Progressive Supranuclear Palsy Other Tauopathy : Pathogenic, FTD : Not Pathogenic Mild frontal and temporal atrophy with neuronal loss, gliosis, enlarged lateral ventricles, and microvacuolation. Accumulated tau in neurons and glia, including neurofibrillary tangles. Elevated 4-repeat (4R) isoforms.

Unknown.
 



rs63751391
Coding
Exon 10
Point, Missense
GGC to GTC
0 Ros et al., 2005
S305I
Argyrophilic Grain Disease FTD : Not Pathogenic, Other Tauopathy : Unclear Pathogenicity Extensive neuronal loss in the medial temporal cortex, hippocampus, and amygdala. No classical neurofibrillary tangles, Pick bodies, or neuritic plaques. Diffuse cytoplasmic tau in neurons, coiled bodies in oligodendrocytes, and argyrophilic grains. The tau-positive structures were composed only of 4-repeat (4R) isoforms. Affects exon 10 splicing, causing an overproduction of 4-repeat (4R) tau isoforms.

Coding
Exon 10
Point, Missense
AGT to ATT
0 Kovacs et al., 2008
S305N
Frontotemporal Dementia FTD : Pathogenic Numerous neurofibrillary tangles including some with an unusual, ring-shaped morphology around the nucleus, especially in the frontal, temporal, insular, and postcentral cortices, as well as in the dentate gyrus. Neurofibrillary tangles in neurons and glia. Stem-loop instability leading to alterations in the ratio of 3-repeat (3R) tau to 4-repeat (4R) tau.

rs63751165
Coding
Exon 10
Point, Missense
AGT to AAT
0 Iijima et al., 1999;
Kobayashi et al., 2002
S305S
Frontotemporal Dementia, Progressive Supranuclear Palsy FTD : Pathogenic, Other Tauopathy : Pathogenic Variable, but associated with cell loss, ballooned neurons, and tau-positive astrocytes, but limited cortical atrophy. Silver-positive neurofibrillary tangles associated with PSP diagnosis but not with FTDP-17 diagnosis. This silent mutation increases the splicing in of exon 10 and results in overproduction of tau isoforms containing four repeats (4R).

rs63750568
Coding
Exon 10
Point, Silent
AGT to AGC
0 Stanford et al., 2000;
Skoglund et al., 2008
L315L
Frontotemporal Dementia FTD : Pathogenic Unknown. Unknown.

rs63751231
Coding
Exon 11
Point, Silent
CTG to CTA
0
L315R
Frontotemporal Dementia, None FTD : Incomplete Penetrance Extensive tau pathology in neurons (Pick-like inclusions) and astrocytes, particularly in the frontotemporal cortex and hippocampus. Tau extracted from the cerebral cortex was present in straight and twisted tau filaments. Recombinant L315R tau protein has a compromised ability to promote microtubule assembly.

rs63749855
Coding
Exon 11
Point, Missense
CTG to CGG
0 van Herpen et al., 2003
K317M
Tauopathy with Parkinsonism and Motor Neuron Disease Other Tauopathy : Pathogenic Severe degeneration of the substantia nigra with extensive neuronal loss and gliosis. No Lewy bodies or Pick’s bodies. Severe neuron loss in the motor bulbar nuclei and anterior horn of the spinal cord. Frequent, diverse inclusions in oligodendrocytes and astrocytes. Phospho-tau-positive pre-tangles and tangles in neurons. Unknown.

rs63750092
Coding
Exon 11
Point, Missense
AAG to ATG
0 Zarranz et al., 2005
K317N
Globular Glial Tauopathy GGT : Pathogenic Lobar atrophy, especially in the inferior frontal gyrus. White-matter pathology, including vacuoles, gliosis, and loss of myelinated fibers. Extensive tau pathology, with tau-positive inclusions in neurons, astrocytes and oligodendrocytes. Distribution of tau pathology consistent with globular glial tauopathy, subtype III. Impaired tubulin polymerization. Altered tau aggregation in an isoform-specific manner; accelerated tau assembly in 4R tau while decreasing tau aggregation, misfolding, and filament assembly in 3R tau.

Coding
Exon 11
Point, Missense
AAG to AAC
0 Tacik et al., 2015
S318L
Alzheimer's Disease, None AD : Unclear Pathogenicity Unknown. Unknown.

rs73314997
Coding
Exon 4a
Point, Missense
TCG to TTG
0 Jin et al., 2012
S320F
Frontotemporal Dementia, Tauopathy consistent with Pick's Disease FTD : Pathogenic Neuropathology consistent with Pick's disease. Focal bilateral atrophy of the anterior temporal lobes with only very mild frontal atrophy; Severe neuronal loss and gliosis in the temporal cortex, cingulate gyrus, entorhinal cortex, and hippocampus. A marked reduction in the ability of tau to promote microtubule assembly; Removal of a potential phosphorylation site in tau.

rs63750635
Coding
Exon 11
Point, Missense
TCC to TTC
0 Rosso et al., 2002
S320Y
Tauopathy consistent with Pick's Disease Other Tauopathy : Pathogenic Unknown. Unknown.

Coding
Exon 11
Point, Missense
0
P332S
Frontotemporal Dementia FTD : Pathogenic Atrophy of primary motor and premotor cortices; neuronal tau-positive lesions mimicking Pick bodies, especially in the dentate gyrus, and containing aggregates of both 3-repeat (3R) and 4-repeat (4R) tau proteins. Reduced capacity to bind microtubules.

Coding
Exon 11
Point, Missense
CCA to TCA
0 Deramecourt et al., 2012
G335S
Frontotemporal Dementia FTD : Pathogenic Degeneration of the frontal and temporal lobes, hippocampus, and substantia nigra. Extensive deposition of tau, neurofibrillary tangles, and neuropil threads, but no Pick bodies. Tau-positive inclusions in neurons and glia. Sarkosyl-insoluble tau showed paired helical and straight filaments, and more irregular rope-like filaments. Reduced ability of tau to promote microtubule assemby.

rs63750095
Coding
Exon 12
Point, Missense
GGC to AGC
0 Spina et al., 2007
G335V
Frontotemporal Dementia FTD : Pathogenic Unknown. Reduced ability of tau to promote microtubule assembly; Increased heparin-induced assembly of recombinant tau into filaments.

rs63750905
Coding
Exon 12
Point, Missense
GGC to GTC
0 Neumann et al., 2005
Q336H
Pick's disease FTD : Pathogenic, Pick's disease : Pathogenic Neuropathology consistent with Pick's disease. Focal cortical atrophy and Pick bodies (cytoplasmic inclusions in neurons that were primarily negative for Gallyas silver stain). Pick bodies contained primarily 3R tau. Pick cells, called “swollen achromatic neurons” or “ballooned neurons,” were frequent in some brain regions. Increased rate and steady-state levels of microtubule polymerization; Greater tau filament assembly and aggregation, especially for 3R tau.  

Coding
Exon 12
Point, Missense
CAG to CAC
0 Tacik et al., 2015
Q336R
Frontotemporal Dementia, Pick's disease FTD : Pathogenic Atrophy of the frontal lobes, anterior temporal lobes, hippocampus, and amygdala. In some areas neuronal loss and astrogliosis were severe, leading to spongiosis. Hyperphosphorylated tau accumulated in swollen (Pick) cells. Intraneuronal inclusions (Pick bodies) containing both 3R and 4R tau and neurofibrillary tangle‐like structures. Increases tau fibrillogenesis. In contrast to most MAPT missense mutations, Q336R increases, rather than decreases, mutant tau's ability to promote microtubule assembly.

rs63750573
Coding
Exon 12
Point, Missense
CAG to CGG
0 Pickering-Brown et al., 2004
V337M
(Seattle Family A)
Frontotemporal Dementia FTD : Pathogenic Neurofibrillary tangles comprised of paired helical filaments without plaques in several regions of the neocortex, amygdala, and parahippocampal gyrus. Accelerates aggregation of tau into filaments. The mutant protein also makes a more favorable substrate for phosphorylation than wild-type 4-repeat (4R) tau.

rs63750570
Coding
Exon 12
Point, Missense
GTG to ATG
3 Poorkaj et al., 1998;
Sumi et al., 1992
E342V
Frontotemporal Dementia FTD : Pathogenic Prominent frontotemporal neuron loss, cytoplasmic tau aggregates, paired helical tau filaments, increased 4-repeat (4R) tau mRNA, increased 4R tau without E2 or E3 inserts (4R0N), decreased 4R tau with these inserts (4R1N and 4R2N). Unknown.

rs63750711
Coding
Exon 12
Point, Missense
GAG to GTG
0 Lippa et al., 2000
S352L
Other Tauopathy Other Tauopathy : Pathogenic Extensive tau neuropathology. Recombinant S352L tau exhibited reduced microtubule binding and accelerated filament formation.

rs63750425
Coding
Exon 12
Point, Missense
TCG to TTG
0 Nicholl et al., 2003
S356T
Frontotemporal Dementia FTD : Pathogenic Frontotemporal and hippocampal atrophy. Some spongiosis. Abundant tau pathology (e.g., mature neurofibrillarly tangles and pretangles, tau-positive threads and grains). β-amyloid pathology largely absent. Unknown.

Coding
Exon 12
Point, Missense
TCC to ACC
0 Momeni et al., 2010
I360V
Parkinson's Disease FTD : , PD : Unclear Pathogenicity Unknown. Unknown.

Coding
Exon 12
Point, Missense
ATC to GTC
0 Schulte et al., 2015
V363I
Frontotemporal Dementia FTD : Incomplete Penetrance Unknown; MRI showed massive brain atrophy. Unknown.

rs63750869
Coding
Exon 12
Point, Missense
GTC to ATC
0 Munoz et al., 2007;
Anfossi et al., 2011
P364S
Frontotemporal Dementia FTD : Pathogenic Neuronal loss and reactive gliosis in many regions, including the nucleus basalis of Meynert, substantia nigra, locus coeruleus, motor cortex, and the anterior horn of the spinal cord. Neuronal tau inclusions, especially globose neurofibrillary tangles with some flame-shaped neurofibrillary tangles. Some Pick body-like inclusions in one case. Reduced ability to promote microtubule assembly compared with wild-type tau and an increased rate of tau aggregation; Increased chromosomal instability and copy-number variations in lymphocytes and fibroblasts of mutation carriers.

Coding
Exon 12
Point, Missense
CCT to TCT
0 Rossi et al., 2012
G366R
Frontotemporal Dementia FTD : Pathogenic Unknown; MRI showed moderate to severe symmetrical cerebral atrophy predominantly involving the frontal lobe with ventricular enlargement. Reduced ability to promote microtubule assembly compared with wild-type tau, but similar aggregation kinetics; Increased chromosomal instability and copy number variations in lymphocytes and fibroblasts of mutation carriers.

Coding
Exon 12
Point, Missense
GGA to AGA
0 Rossi et al., 2012
K369I
Frontotemporal Dementia, Tauopathy consistent with Pick's Disease FTD : Pathogenic Brain atrophy, especially in the temporal lobes. Numerous tau-positive Pick bodies and Pick cells indistinguishable from those of sporadic Pick's disease in the neocortex, hippocampus, and subcortical brain regions. Recombinant tau proteins with the K369I mutation showed reduced ability to promote microtubule assembly.

rs63751264
Coding
Exon 12
Point, Missense
AAA to ATA
0 Neumann et al., 2001
R370W
None FTD : Not Pathogenic Not applicable. Unknown.

rs17651549
Coding
Exon 4a
Point, Missense
CGG to TGG
0 Lilius et al., 1999
G389R
(G>A)
Frontotemporal Dementia, Pick's disease FTD : Pathogenic, Other Tauopathy : Pathogenic Severe frontal lobe atrophy; neuronal loss; astrocytosis; tissue vacuolation. Recombinant G389R tau showed a reduced ability to promote microtubule assembly and an increased susceptibility to calpain I digestion.

rs63750512
Coding
Exon 13
Point, Missense
GGG to AGG
0 Pickering-Brown et al., 2000
G389R
(G>C)
Frontotemporal Dementia FTD : Pathogenic Numerous neocortical tau-positive Pick body-like inclusions and filamentous axonal inclusions.   Recombinant G389R tau showed a reduced ability to promote microtubule assembly.

rs63750512
Coding
Exon 13
Point, Missense
GGG to CGG
0 Murrell et al., 1999;
Ghetti et al., 2000;
Rossi et al., 2008
R406W
Alzheimer's Disease, Frontotemporal Dementia FTD : Pathogenic Bilateral frontotemporal atrophy. Neuronal loss, gliosis, and abundant tau-positive inclusions, including neurofibrillary tangles. Generally sparse or absent Aβ plaques. Possible impairment in the ability to promote microtubule assembly.

rs63750424
Coding
Exon 13
Point, Missense
CGG to TGG
5 Hutton et al., 1998
L410F
Alzheimer's Disease AD : Not Pathogenic Not applicable. Unknown; predicted probably damaging in silico.

Coding
Exon 6
Point, Missense
CTT to TTT
0 Piccoli et al., 2016
N410H
Corticobasal Degeneration Other Tauopathy : Pathogenic Mild atrophy of the superior frontal cortex and enlargement of the lateral ventricles. Loss of neuromelanin in the midbrain. Abundant 4R tau-positive astrocytic plaques and numerous threads in the gray and white matter. Abundant ballooned neurons in the superior frontal cortex. Significant TDP-43 pathology, especially in the basal ganglia. Increase in the 4R/3R tau-mRNA ratio in patient brain. Recombinant tau with the N410H mutation had increased tau filament formation compared with wild-type tau, a decreased rate of microtubule assembly, and reduced overall microtubule polymerization.

Coding
Exon 13
Point, Missense
AAT to CAT
0 Kouri et al., 2014
S427F
Alzheimer's Disease, None, Parkinson's Disease Dementia PDD : Unclear Pathogenicity, AD : Unclear Pathogenicity Unknown. Unknown; predicted to be probably damaging in silico.

rs143956882
Coding
Point, Missense
TCC to TTC
0 Schulte et al., 2015
T427M
Frontotemporal Dementia, Parkinson's Disease FTD : Pathogenic, PD : Unclear Pathogenicity Unknown; MRI showed moderate frontotemporal atrophy. Unknown.

rs63750991
Coding
Exon 13
Point, Missense
ACG to ATG
0 Giaccone et al., 2005
H441Y
None FTD : Not Pathogenic Not applicable. Unknown.

rs2258689
Coding
Exon 6
Point, Missense
CAC to TAC
0 Poorkaj et al., 1998
S447P
None FTD : Not Pathogenic Not applicable. Unknown.

rs10445337
Coding
Exon 6
Point, Missense
TCC to CCC
0 Poorkaj et al., 1998
R448*
Parkinson's Disease PD : Unclear Pathogenicity Unknown. Unknown.

rs200099007
Coding
Point, Nonsense
CGA to TGA
0 Schulte et al., 2015
T504T
None FTD : Not Pathogenic Not applicable. Unknown.

rs62063845
Coding
Exon 8
Point, Silent
ACT to ACC
0 Higgins et al., 1999
P511R
None FTD : Not Pathogenic Not applicable. Unknown.

Coding
Point, Missense
0 Schulte et al., 2015
P512H
Alzheimer's Disease AD : Not Pathogenic Not applicable. Unknown; predicted probably damaging in silico.

rs192236920
Coding
Exon 8
Point, Missense
CCC to CAC
0 Piccoli et al., 2016
Duplication 17q21.31
Alzheimer's Disease Other Tauopathy : Pathogenic Neurofibrillary tangles in the hippocampus and entorhinal cortex. Aβ deposits were absent. The genomic duplication was associated with a 60-90% increase in the mRNA levels of MAPT.

Both
Duplicaton
0 Le Guennec et al., 2016
IVS9-10 G>T
(g(-10)t)
Frontotemporal Dementia FTD : Pathogenic Unknown. This intronic mutation stregthens the splice acceptor site, resulting in more frequent inclusion of exon 10 into mRNA transcripts.

rs63749974
Non-Coding
Intron 9
Point
G to T
0 Malkani et al., 2006
IVS9-15 T>C
Frontotemporal Dementia FTD : Unclear Pathogenicity Severe frontotemporal atrophy with relative sparing of the motor and visual cortices. Severe hippocampal pathology with neurons replaced by a dense band of astrocytic gliosis. Abundant tau pathology, primarily consisting of 3-repeat (3R) tau isoforms, consistent with Pick's disease. Ghost tangles in the cortex. When co-transfected with another splice-site variant, this mutation decreases the inclusion of exon 10, generating more E10- transcripts and resulting in an overproduction of 3-repeat (3R) tau isoforms.

Non-Coding
Intron 9
Point
T to C
0 Anfossi et al., 2011
IVS10+3 G>A
Frontotemporal Dementia FTD : Pathogenic Abundant filamentous tau deposits in the neocortex, some in subcortical nuclei, brainstem, and spinal cord. Deposits in neurons and glia, especially oligodendrocytes. Tau filaments are twisted and consist of 4-repeat (4R) tau isoforms. Destabilizes a stem-loop structure that regulates the alternative splicing of exon 10r, resulting in more frequent inclusion of exon 10 and an increased proportion of four-repeat (4R) tau isoforms..

rs63750013
Non-Coding
Intron 10
Point
G to A
0 Spillantini et al., 1998
IVS10+4 A>C
Frontotemporal Dementia FTD : Unclear Pathogenicity Severe frontotemporal atrophy with relative sparing of the motor and visual cortices. Severe hippocampal pathology with neurons replaced by a dense band of astrocytic gliosis. Abundant tau pathology, primarily consisting of 3-repeat (3R) tau isoforms, consistent with Pick's disease. Ghost tangles in the cortex. When co-transfected with another splice-site variant, decreases the inclusion of exon 10, resulting in an overproduction of 3-repeat (3R) tau isoforms.

Non-Coding
Intron 10
Point
A to C
0 Anfossi et al., 2011
IVS10+11 T>C
Frontotemporal Dementia FTD : Pathogenic Severe neuronal loss in the frontal and temporal cortices, globus pallidus, substantia nigra, red nucleus, and dentate nucleus. Tau-positive fibrillar structures in neurons and glia. Alters the splicing of exon 10, resulting in increased 4-repeat (4R) tau relative to 3-repeat (3R) tau.

rs63751394
Non-Coding
Intron 10
Point, Missense
T to C
0 Kowalska et al., 2002;
Miyamoto et al., 2001
IVS10+12 C>T
Frontotemporal Dementia FTD : Pathogenic Tau aggregates in neurons and glia; Isolated tau filaments with twisted, ribbon-like morphology comprised of hyperphosphorylated 4-repeat (4R) tau isoforms. Destabilizes a stem-loop structure that regulates the alternative splicing of exon 10, resulting in more frequent inclusion of exon 10 and an increased proportion of four-repeat (4R) tau isoforms.

rs63750916
Non-Coding
Intron 10
Point
C to T
0 Yasuda et al., 2000
IVS10+13 A>G
Frontotemporal Dementia FTD : Pathogenic Severe "knife‐edge" atrophy in the frontal and temporal lobes; Frequent neurofibrillary and glial tangles; Occasional ballooned neurons and damage to the substantia nigra. Destabilizes a stem-loop structure that regulates the alternative splicing of exon 10, resulting in more frequent inclusion of exon 10 and an increased proportion of four-repeat (4R) tau isoforms.

rs63750308
Non-Coding
Intron 10
Point
A to G
0 Hutton et al., 1998
IVS10+14 C>T
Frontotemporal Dementia FTD : Pathogenic Atrophy and spongiform changes in the frontotemporal cortex; Neuronal loss and gliosis in the substantia nigra and amygdala; Deposition of 4R tau. Destabilizes a stem-loop structure that regulates alternative splicing of exon 10, causing more frequent inclusion of exon 10 and leading to an increase in the proportion of four-repeat (4R) tau isoforms.

rs63750972
Non-Coding
Intron 10
Point
C to T
0 Hutton et al., 1998
IVS10+15 A>C
Frontotemporal Dementia FTD : Pathogenic Unknown; imaging showed bilateral anterior temporal lobe atrophy and hypometabolism. Destabilizes a stem-loop structure that regulates the alternative splicing of exon 10, resulting in more frequent inclusion of exon 10 and an increased proportion of four-repeat (4R) tau isoforms.

Non-Coding
Intron 10
Point
A to C
0 McCarthy et al., 2015
IVS10+16 C>T
Alzheimer's Disease, Frontotemporal Dementia, Progressive Supranuclear Palsy FTD : Pathogenic Neuronal loss, gray-matter gliosis, and neuropil vacuolation in both the frontal and temporal lobes. Balloon neurons in the cortex and degeneration of the substantia nigra with free melanin. Tau-positive neurons. Destabilizes a stem-loop structure that regulates the alternative splicing of exon 10, resulting in more frequent inclusion of exon 10 and an increased proportion of four-repeat (4R) tau isoforms.

rs63751011
Non-Coding
Intron 10
Point
C to T
1 Hutton et al., 1998
IVS10+19 C>G
Frontotemporal Dementia FTD : Pathogenic Frontal lobe atrophy; Frontal hypoperfusion. Alters the splicing of exon 10, resulting in increased 3-repeat (3R) tau isoforms. Elevated 3R tau was shown to decrease microtubule assembly.

rs63750162
Non-Coding
Intron 10
Point
C to G
0 Stanford et al., 2003
IVS10+25 C>T
None FTD : Not Pathogenic, AD : Not Pathogenic Not applicable. Unknown.

rs63750117
Non-Coding
Intron 10
Point
C to T
0 Roks et al., 1999
IVS10+29 G>A
None FTD : Not Pathogenic Not applicable. IVS10 + 29 G>A does not appear to alter the splicing of exon 10.

rs63751443
Non-Coding
Intron 10
Point
G to A
0 D'Souza et al., 1999;
Roks et al., 1999