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UniProtKB/Swiss-Prot P05067: Variant p.Leu723Pro

Amyloid-beta precursor protein
Gene: APP
Variant information

Variant position:  723
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  LP/P [Disclaimer]
The variants are classified into three categories: LP/P, LB/B and US.
  • LP/P: likely pathogenic or pathogenic.
  • LB/B: likely benign or benign.
  • US: uncertain significance

Residue change:  From Leucine (L) to Proline (P) at position 723 (L723P, p.Leu723Pro).
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

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:  723
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:   IGLMVGGVVIATVIVITLVM  L KKKQYTSIHHGVVEVDAAVT
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                         IGLMVGGVVIATVI-VITLVMLKKKQYTSIH-HGVVEVD---AAVT

Chimpanzee                    IGLMVGGVVIATVI-VITLVMLKKKQYTSIH-HGVVEVD--

Mouse                         IGLMVGGVVIATVI-VITLVMLKKKQYTSIH-HGVVEVD--

Rat                           IGLMVGGVVIATVI-VITLVMLKKKQYTSIH-HGVVEVD--

Pig                           IGLMVGGVVIATVI-VITLVMLKKKQYTSIH-HGVVEVD--

Caenorhabditis elegans        QPYVLASAMFITAICIIAFAITNARRRRAM--RGFIEVD--

Drosophila                    FTLSFAGIALMAAV-FVGVAVAKWRTSRSPHAQGFIEVDQN

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 precursor 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
Chain 721 – 770 Gamma-secretase C-terminal fragment 50
Topological domain 723 – 770 Cytoplasmic
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
Modified residue 743 – 743 Phosphothreonine; by CDK5 and MAPK10
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 amyloid-beta protein 42/total amyloid-beta ratio.
Mutagenesis 717 – 717 V -> K. Decreased amyloid-beta protein 42/total amyloid-beta ratio.
Mutagenesis 717 – 717 V -> M. Increased amyloid-beta protein 42/40 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 amyloid-beta protein 42 secretion.
Mutagenesis 739 – 739 D -> A. No cleavage by caspases during apoptosis.
Mutagenesis 739 – 739 D -> N. No effect on FADD-induced apoptosis.
Mutagenesis 743 – 743 T -> A. Greatly reduces the binding to SHC1 and APBB family members; no effect on NGF-stimulated neurite extension. Loss of phosphorylation by LRRK2.
Mutagenesis 743 – 743 T -> E. Reduced NGF-stimulated neurite extension. No effect on APP maturation.
Beta strand 721 – 725


Literature citations

Novel Leu723Pro amyloid precursor protein mutation increases amyloid beta42(43) peptide levels and induces apoptosis.
Kwok J.B.J.; Li Q.X.; Hallupp M.; Whyte S.; Ames D.; Beyreuther K.; Masters C.L.; Schofield P.R.;
Ann. Neurol. 47:249-253(2000)
Cited for: VARIANT AD1 PRO-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.