rs63750424

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PP5_Very_StrongBP4

The NM_001377265.1(MAPT):c.2392C>T(p.Arg798Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,461,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R798P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

MAPT
NM_001377265.1 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12O:1

Conservation

PhyloP100: 2.20

Publications

598 publications found

Variant links:

Genes affected

MAPT (HGNC:6893): (microtubule associated protein tau) This gene encodes the microtubule-associated protein tau (MAPT) whose transcript undergoes complex, regulated alternative splicing, giving rise to several mRNA species. MAPT transcripts are differentially expressed in the nervous system, depending on stage of neuronal maturation and neuron type. MAPT gene mutations have been associated with several neurodegenerative disorders such as Alzheimer's disease, Pick's disease, frontotemporal dementia, cortico-basal degeneration and progressive supranuclear palsy. [provided by RefSeq, Jul 2008]

MAPT Gene-Disease associations (from GenCC):

Pick disease
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
semantic dementia
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
supranuclear palsy, progressive, 1
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
late-onset Parkinson disease
Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
progressive supranuclear palsy-parkinsonism syndrome
Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp

MAPT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PP5

Variant 17-46024061-C-T is Pathogenic according to our data. Variant chr17-46024061-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 14247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.2905081). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPT	NM_001377265.1 link	c.2392C>T	p.Arg798Trp	missense_variant	Exon 13 of 13	ENST00000262410.10	NP_001364194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPT	ENST00000262410.10 link	c.2392C>T	p.Arg798Trp	missense_variant	Exon 13 of 13	1	NM_001377265.1	ENSP00000262410.6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251284

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461828

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000198

AC:

AN:

1111990

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000268

Hom.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5Other:1

VIB Department of Molecular Genetics, University of Antwerp

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 14, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate that R406W cells show a decreased level of phosphorylation and an inability to bind to microtubules, resulting in accumulation in the cytoplasm (PMID: 11756436, 10820221); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23105105, 30279455, 30562452, 31836585, 29370822, 33061333, 34158384, 33427744, 23383383, 22368988, 18803694, 10820221, 24150109, 20634584, 23338682, 19304664, 21339331, 11102510, 18992292, 21849646, 22787795, 20377816, 26581847, 26028272, 25377499, 26734663, 25942996, 29253099, 11278002, 12368474, 11889249, 18284428, 9641683, 14517953, 10514099, 18587238, 20683187, 23727082, 31127772, 30924900, 32843152, 20662935, 11756436, 35790423, 36171642, 28738127, 37431188) -

Nov 26, 2014

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Frontotemporal dementia

Pathogenic:4

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 406 of the MAPT protein (p.Arg406Trp). This variant is present in population databases (rs63750424, gnomAD 0.004%). This missense change has been observed in individuals with behavioral variant frontotemporal dementia (bvFTD), Alzheimer's disease, and/or mixed dementia with parkinsonism (PMID: 9382467, 9641683, 11117542, 11889249, 23383383, 23727082, 25942996, 26028272). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14247). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MAPT protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects MAPT function (PMID: 10797541, 11102510, 11756436, 19304664, 21339331, 24150109). For these reasons, this variant has been classified as Pathogenic. -

Nov 01, 2003

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Dec 12, 2023

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 12, 2025

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG criteria used: PS3, PS4, PP1_strong, PP4, BP4 -

Pick disease;C0338451:Frontotemporal dementia;C1850077:Progressive supranuclear palsy-parkinsonism syndrome;C3160718:Parkinson disease, late-onset;C4551863:Supranuclear palsy, progressive, 1

Pathogenic:1

Mar 15, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

MAPT-related disorder

Pathogenic:1

Sep 18, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The MAPT c.2221C>T variant is predicted to result in the amino acid substitution p.Arg741Trp. The variant is also referred to as c.1216C>T (p.Arg406Trp) using a different transcript (NM_005910.5). This variant has been extensively reported in individuals with behavioral variant frontotemporal dementia (bvFTD), Alzheimer Disease, or dementia with parkinsonism (Tipton et al. 2022. PubMed ID: 35790423; Koriath et al. 2020. PubMed ID: 30279455; Kunkle et al. 2017. PubMed ID: 28738127). For example, this variant has been reported in the heterozygous state to be causative of frontotemporal dementia in a large family with a history of the disease (Hutton et al. 1998. PubMed ID: 9641683). It was also reported in the heterozygous state to be pathogenic in a large family with early-onset Alzheimer Disease (EOAD)-like presentation (Carney et al. 2014. PubMed ID: 23727082). One report described this variant in the homozygous state in an individual with early-onset bvFTD who developed symptoms 20 years before mean family symptom onset, suggesting a dose-dependent effect on disease risk (Ng et al. 2015. PMID: 26734663). It is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD; and has been consistently classified as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/14247/). This variant is interpreted as pathogenic. -

Progressive supranuclear palsy-parkinsonism syndrome

Pathogenic:1

May 21, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. (N) 0112 - Variants in this gene are known to have reduced penetrance (PMID: 20301678). (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan (exon 14). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (4 heterozygotes, 0 homozygotes). (P) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (2 heterozygotes, 0 homozygotes). (N) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0504 - Same amino acid change has been observed in mammals. (B) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. Multiple patients reported with phenotypic heterogeneity, presenting frontotemporal dementia with or without parkinsonism, early onset dementia and Alzheimer disease (PMID: 23727082). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.79

D;.;.;.;.;.;.;.;.;D;.;.

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

D;D;D;D;D;D;D;.;.;.;.;.

M_CAP

Benign

0.027

MetaRNN

Benign

0.29

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.5

L;.;.;.;.;.;.;.;.;L;.;.

PhyloP100

2.2

PrimateAI

Benign

0.45

PROVEAN

Pathogenic

-5.2

D;D;D;D;D;.;.;D;D;.;.;.

REVEL

Benign

0.29

Sift

Uncertain

0.013

D;D;D;D;D;.;.;D;D;.;.;.

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0

D;D;D;.;D;D;D;D;D;D;D;.

Vest4

0.17

MutPred

0.42

Loss of disorder (P = 0.0292);.;.;.;.;.;.;.;.;Loss of disorder (P = 0.0292);.;.;

MVP

0.84

MPC

2.1

ClinPred

0.98

GERP RS

3.4

Varity_R

0.78

gMVP

0.77

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over