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UniProtKB/Swiss-Prot P05067: Variant p.Glu693Gly

Amyloid-beta precursor protein
Gene: APP
Variant information

Variant position:  693
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 Glutamate (E) to Glycine (G) at position 693 (E693G, p.Glu693Gly).
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:  Change from medium size and acidic (E) to glycine (G)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -2
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:  Alzheimer disease 1 (AD1) [MIM:104300]: A familial early-onset form of Alzheimer disease. It can be associated with cerebral amyloid angiopathy. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituents of these plaques are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that are produced by the proteolysis of the transmembrane APP protein. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products, such as C31, are also implicated in neuronal death. {ECO:0000269|PubMed:10097173, ECO:0000269|PubMed:10631141, ECO:0000269|PubMed:10656250, ECO:0000269|PubMed:10665499, ECO:0000269|PubMed:10677483, ECO:0000269|PubMed:10867787, ECO:0000269|PubMed:11063718, ECO:0000269|PubMed:11311152, ECO:0000269|PubMed:11528419, ECO:0000269|PubMed:12034808, ECO:0000269|PubMed:1302033, ECO:0000269|PubMed:1303239, ECO:0000269|PubMed:1303275, ECO:0000269|PubMed:1415269, ECO:0000269|PubMed:1465129, ECO:0000269|PubMed:15201367, ECO:0000269|PubMed:15365148, ECO:0000269|PubMed:15668448, ECO:0000269|PubMed:1671712, ECO:0000269|PubMed:1678058, ECO:0000269|PubMed:1908231, ECO:0000269|PubMed:1925564, ECO:0000269|PubMed:1944558, ECO:0000269|PubMed:8267572, ECO:0000269|PubMed:8290042, ECO:0000269|PubMed:8476439, ECO:0000269|PubMed:8577393, ECO:0000269|PubMed:8886002, ECO:0000269|PubMed:9328472, ECO:0000269|PubMed:9754958}. 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 AD1.
Any additional useful information about the variant.

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

Sequence information

Variant position:  693
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  770
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.

Human                         AEFRHD----------------SGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA

Chimpanzee                    AEFRHD----------------SGYEVHHQKLVFFAEDVGS

Mouse                         AEFGHD----------------SGFEVRHQKLVFFAEDVGS

Rat                           AEFGHD----------------SGFEVRHQKLVFFAEDVGS

Pig                           AEFRHD----------------SGYEVHHQKLVFFAEDVGS

Caenorhabditis elegans        IEPIIDEP--------------ASFY-RHDKLIQSPEVERS


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 18 – 770 Amyloid-beta precursor protein
Chain 672 – 770 C99
Chain 672 – 713 Amyloid-beta protein 42
Chain 672 – 711 Amyloid-beta protein 40
Chain 688 – 770 C83
Peptide 688 – 713 P3(42)
Peptide 688 – 711 P3(40)
Chain 691 – 770 C80
Topological domain 18 – 701 Extracellular
Metal binding 677 – 677 Copper or zinc 2
Metal binding 681 – 681 Copper or zinc 2
Metal binding 684 – 684 Copper or zinc 2
Metal binding 685 – 685 Copper or zinc 2
Site 704 – 704 Implicated in free radical propagation
Site 706 – 706 Susceptible to oxidation
Glycosylation 681 – 681 O-linked (HexNAc...) tyrosine; partial
Alternative sequence 306 – 770 Missing. In isoform APP305.
Mutagenesis 676 – 676 R -> G. 60-70% zinc-induced amyloid-beta protein 28 aggregation.
Mutagenesis 681 – 681 Y -> F. 60-70% zinc-induced amyloid-beta protein 28 aggregation.
Mutagenesis 684 – 684 H -> R. Only 23% zinc-induced amyloid-beta protein 28 aggregation.
Mutagenesis 695 – 695 V -> C. Causes formation of an artifactual disulfide bond with PSEN1.
Mutagenesis 704 – 704 G -> V. Reduced protein oxidation. No hippocampal neuron toxicity.
Mutagenesis 706 – 706 M -> L. Reduced lipid peroxidation inhibition.
Mutagenesis 706 – 706 M -> V. No free radical production. No hippocampal neuron toxicity.
Beta strand 692 – 694

Literature citations

Linkage and mutational analysis of familial Alzheimer disease kindreds for the APP gene region.
Kamino K.; Orr H.T.; Payami H.; Wijsman E.M.; Alonso M.E.; Pulst S.M.; Anderson L.; O'Dahl S.; Nemens E.; White J.A.; Sadovnick A.D.; Ball M.J.; Kaye J.; Warren A.; McInnis M.G.; Antonarakis S.E.; Korenberg J.R.; Sharma V.; Kukull W.; Larson E.; Heston L.L.; Martin G.M.; Bird T.D.; Schellenberg G.D.;
Am. J. Hum. Genet. 51:998-1014(1992)
Cited for: VARIANT AD1 GLY-693;

The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation.
Nilsberth C.; Westlind-Danielsson A.; Eckman C.B.; Condron M.M.; Axelman K.; Forsell C.; Stenh C.; Luthman J.; Teplow D.B.; Younkin S.G.; Naeslund J.; Lannfelt L.;
Nat. Neurosci. 4:887-893(2001)
Cited for: VARIANT AD1 GLY-693;

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.