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UniProtKB/Swiss-Prot P10636: Variant p.Pro618Leu

Microtubule-associated protein tau
Gene: MAPT
Variant information

Variant position:  618
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  Disease [Disclaimer]
The variants are classified into three categories: Disease, Polymorphism and Unclassified.
  • Disease: Variants implicated in disease according to literature reports.
  • Polymorphism: Variants not reported to be implicated in disease.
  • Unclassified: Variants with uncertain implication in disease according to literature reports. Evidence against or in favor of a pathogenic role is limited and/or conflicting.

Residue change:  From Proline (P) to Leucine (L) at position 618 (P618L, p.Pro618Leu).
Indicates the amino acid change of the variant. The one-letter and three-letter codes for amino acids used in UniProtKB/Swiss-Prot are those adopted by the commission on Biochemical Nomenclature of the IUPAC-IUB.

Physico-chemical properties:  Similar physico-chemical property. Both residues are medium size and hydrophobic.
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -3
The score within a Blosum matrix for the corresponding wild-type to variant amino acid change. The log-odds score measures the logarithm for the ratio of the likelihood of two amino acids appearing by chance. The Blosum62 substitution matrix is used. This substitution matrix contains scores for all possible exchanges of one amino acid with another:
  • Lowest score: -4 (low probability of substitution).
  • Highest score: 11 (high probability of substitution).
More information can be found on the following page

Involvement in disease:  Frontotemporal dementia (FTD) [MIM:600274]: A form of dementia characterized by pathologic finding of frontotemporal lobar degeneration, presenile dementia with behavioral changes, deterioration of cognitive capacities and loss of memory. In some cases, parkinsonian symptoms are prominent. Neuropathological changes include frontotemporal atrophy often associated with atrophy of the basal ganglia, substantia nigra, amygdala. In most cases, protein tau deposits are found in glial cells and/or neurons. {ECO:0000269|PubMed:10208578, ECO:0000269|PubMed:10214944, ECO:0000269|PubMed:10374757, ECO:0000269|PubMed:10489057, ECO:0000269|PubMed:10553987, ECO:0000269|PubMed:10802785, ECO:0000269|PubMed:11071507, ECO:0000269|PubMed:11117541, ECO:0000269|PubMed:11278002, ECO:0000269|PubMed:11585254, ECO:0000269|PubMed:11889249, ECO:0000269|PubMed:11906000, ECO:0000269|PubMed:11921059, ECO:0000269|PubMed:12473774, ECO:0000269|PubMed:12509859, ECO:0000269|PubMed:14517953, ECO:0000269|PubMed:15883319, ECO:0000269|PubMed:16240366, ECO:0000269|PubMed:26086902, ECO:0000269|PubMed:9629852, ECO:0000269|PubMed:9641683, ECO:0000269|PubMed:9736786, ECO:0000269|PubMed:9789048, ECO:0000269|PubMed:9973279}. Note=The disease is caused by mutations affecting the gene represented in this entry.
The name and a short description of the disease associated with the variant. For more information about the disease, the user can refer to OMIM, following the link provided after the disease acronym.

Variant description:  In FTD; most common mutation; reduction in the ability to promote microtubule assembly; accelerates aggregation of tau into filaments.
Any additional useful information about the variant.

Other resources:  
Links to websites of interest for the variant.

Sequence information

Variant position:  618
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  758
The length of the canonical sequence.

The residue change on the sequence. Unless the variant is located at the beginning or at the end of the protein sequence, both residues upstream (20) and downstream (20) of the variant will be shown.

Residue conservation: 
The multiple alignment of the region surrounding the variant against various orthologous sequences.









Sequence annotation in neighborhood:  
The regions or sites of interest surrounding the variant. In general the features listed are posttranslational modifications, binding sites, enzyme active sites, local secondary structure or other characteristics reported in the cited references. The "Sequence annotation in neighborhood" lines have a fixed format:
  • Type: the type of sequence feature.
  • Positions: endpoints of the sequence feature.
  • Description: contains additional information about the feature.

Chain 2 – 758 Microtubule-associated protein tau
Repeat 592 – 622 Tau/MAP 2
Region 561 – 685 Microtubule-binding domain
Site 607 – 607 Not glycated
Site 611 – 611 Not glycated
Site 615 – 615 Not glycated
Site 628 – 628 Not glycated
Site 634 – 634 Not glycated
Site 638 – 638 Not glycated
Modified residue 598 – 598 N6-acetyllysine; alternate
Modified residue 602 – 602 Phosphoserine; by PHK
Modified residue 607 – 607 N6-acetyllysine
Modified residue 610 – 610 Phosphoserine
Modified residue 615 – 615 N6-acetyllysine; alternate
Modified residue 622 – 622 Phosphoserine; by PHK
Modified residue 628 – 628 N6,N6-dimethyllysine; alternate
Modified residue 628 – 628 N6-acetyllysine; alternate
Modified residue 634 – 634 N6-acetyllysine; alternate
Modified residue 638 – 638 N6-acetyllysine; alternate
Glycosylation 598 – 598 N-linked (Glc) (glycation) lysine; in PHF-tau; in vitro
Disulfide bond 608 – 639
Cross 598 – 598 Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin); alternate
Cross 615 – 615 Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin); alternate
Cross 628 – 628 Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin); in PHF-tau
Cross 634 – 634 Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin); alternate
Cross 638 – 638 Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin); alternate
Alternative sequence 592 – 622 Missing. In isoform Tau-A, isoform Tau-B, isoform Tau-C and isoform Fetal-tau.
Beta strand 618 – 620

Literature citations

Segregation of a missense mutation in the microtubule-associated protein tau gene with familial frontotemporal dementia and parkinsonism.
Dumanchin C.; Camuzat A.; Campion D.; Verpillat P.; Hannequin D.; Dubois B.; Saugier-Veber P.; Martin C.; Penet C.; Charbonnier F.; Agid Y.; Frebourg T.; Brice A.;
Hum. Mol. Genet. 7:1825-1829(1998)
Cited for: VARIANT FTD LEU-618;

Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17.
Hutton M.; Lendon C.L.; Rizzu P.; Baker M.; Froelich S.; Houlden H.; Pickering-Brown S.; Chakraverty S.; Isaacs A.; Grover A.; Hackett J.; Adamson J.; Lincoln S.; Dickson D.; Davies P.; Petersen R.C.; Stevens M.; de Graaff E.; Wauters E.; van Baren J.; Hillebrand M.; Joosse M.; Kwon J.M.; Nowotny P.; Che L.K.; Norton J.; Morris J.C.; Reed L.A.; Trojanowski J.; Basun H.; Lannfelt L.; Neystat M.; Fahn S.; Dark F.; Tannenberg T.; Dodd P.R.; Hayward N.; Kwok J.B.J.; Schofield P.R.; Andreadis A.; Snowden J.; Craufurd D.; Neary D.; Owen F.; Oostra B.A.; Hardy J.; Goate A.; van Swieten J.; Mann D.; Lynch T.; Heutink P.;
Nature 393:702-705(1998)
Cited for: VARIANTS FTD VAL-589; LEU-618 AND TRP-723;

Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17.
Clark L.N.; Poorkaj P.; Wszolek Z.; Geschwind D.H.; Nasreddine Z.S.; Miller B.; Li D.; Payami H.; Awert F.; Markopoulou K.; Andreadis A.; D'Souza I.; Lee V.M.-Y.; Reed L.; Trojanowski J.Q.; Zhukareva V.; Bird T.; Schellenberg G.; Wilhelmsen K.C.;
Proc. Natl. Acad. Sci. U.S.A. 95:13103-13107(1998)
Cited for: VARIANTS FTD LYS-596 AND LEU-618;

High prevalence of mutations in the microtubule-associated protein tau in a population study of frontotemporal dementia in the Netherlands.
Rizzu P.; Van Swieten J.C.; Joosse M.; Hasegawa M.; Stevens M.; Tibben A.; Niermeijer M.F.; Hillebrand M.; Ravid R.; Oostra B.A.; Goedert M.; van Duijn C.M.; Heutink P.;
Am. J. Hum. Genet. 64:414-421(1999)
Cited for: VARIANTS FTD VAL-589; LYS-597 DEL; LEU-618 AND TRP-723;

Accelerated filament formation from tau protein with specific FTDP-17 missense mutations.
Nacharaju P.; Lewis J.; Easson C.; Yen S.; Hackett J.; Hutton M.; Yen S.H.;
FEBS Lett. 447:195-199(1999)
Cited for: VARIANTS FTD LEU-618; MET-654 AND TRP-723;

Disclaimer: Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. They are not in any way intended to be used as a substitute for professional medical advice, diagnostic, treatment or care.