UniProtKB/Swiss-Prot P05067: Variant p.Ile716Val

Amyloid beta A4 protein
Gene: APP
Chromosomal location: 21q21.2
Variant information

Variant position:  716
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 have been found in patients and disease-association is reported in literature. However, this classification is not a definitive assessment of variant pathogenicity.
  • Polymorphism: No disease-association has been reported.
  • Unclassified: Variants have been found in patients but disease-association remains unclear.

Residue change:  From Isoleucine (I) to Valine (V) at position 716 (I716V, p.Ile716Val).
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:  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 constituent of these plaques is the neurotoxic amyloid-beta-APP 40-42 peptide (s), derived proteolytically from the transmembrane precursor protein APP by sequential secretase processing. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products such as C31 derived from APP, are also implicated in neuronal death. {ECO:0000269|PubMed:10097173, ECO:0000269|PubMed:10631141, ECO:0000269|PubMed:10665499, ECO:0000269|PubMed:10867787, ECO:0000269|PubMed:11063718, 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: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: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.



Sequence information

Variant position:  716
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  770
The length of the canonical sequence.

Location on the sequence:   GSNKGAIIGLMVGGVVIATV  I VITLVMLKKKQYTSIHHGVV
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                         GSNKGAIIGLMVGGVVIATVI-VITLVMLKKKQYTSIH-HGVV

Chimpanzee                    GSNKGAIIGLMVGGVVIATVI-VITLVMLKKKQYTSIH-HG

Mouse                         GSNKGAIIGLMVGGVVIATVI-VITLVMLKKKQYTSIH-HG

Rat                           GSNKGAIIGLMVGGVVIATVI-VITLVMLKKKQYTSIH-HG

Pig                           GSNKGAIIGLMVGGVVIATVI-VITLVMLKKKQYTSIH-HG

Caenorhabditis elegans        RSASSVFQPYVLASAMFITAICIIAFAITNARRRRAM--RG

Drosophila                    KEGRNVYFTLSFAGIALMAAV-FVGVAVAKWRTSRSPHAQG

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.

TypePositionsDescription
Chain 18 – 770 Amyloid beta A4 protein
Chain 672 – 770 C99
Chain 688 – 770 C83
Chain 691 – 770 C80
Chain 712 – 770 Gamma-secretase C-terminal fragment 59
Chain 714 – 770 Gamma-secretase C-terminal fragment 57
Transmembrane 700 – 723 Helical
Site 704 – 704 Implicated in free radical propagation
Site 706 – 706 Susceptible to oxidation
Modified residue 729 – 729 Phosphothreonine
Modified residue 730 – 730 Phosphoserine; by APP-kinase I
Glycosylation 697 – 697 O-linked (GalNAc...)
Alternative sequence 306 – 770 Missing. In isoform APP305.
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.
Mutagenesis 717 – 717 V -> CS. Unchanged beta-APP42/total APP-beta ratio.
Mutagenesis 717 – 717 V -> FGI. Increased beta-APP42/beta-APP40 ratio.
Mutagenesis 717 – 717 V -> K. Decreased beta-APP42/total APP-beta ratio.
Mutagenesis 717 – 717 V -> M. Increased beta-APP42/beta-APP40 ratio. No change in apoptosis after caspase cleavage.
Mutagenesis 728 – 728 Y -> A. No effect on APBA1 nor APBB1 binding. Greatly reduces the binding to APPBP2. APP internalization unchanged. No change in beta-APP42 secretion.


Literature citations

A new pathogenic mutation in the APP gene (I716V) increases the relative proportion of A beta 42(43).
Eckman C.B.; Mehta N.D.; Crook R.; Perez-Tur J.; Prihar G.; Pfeiffer E.; Graff-Radford N.; Hinder P.; Yager D.; Zenk B.; Refolo L.M.; Prada C.M.; Younkin S.G.; Hutton M.; Hardy J.;
Hum. Mol. Genet. 6:2087-2089(1997)
Cited for: VARIANT AD1 VAL-716;

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.