UniProtKB/Swiss-Prot P49768: Variant p.Ala426Pro

Gene: PSEN1
Chromosomal location: 14q24.3
Variant information

Variant position:  426
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 Alanine (A) to Proline (P) at position 426 (A426P, p.Ala426Pro).
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 small size and hydrophobic (A) to medium size and hydrophobic (P)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -1
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 3 (AD3) [MIM:607822]: A familial early-onset form of Alzheimer disease. 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:10025789, ECO:0000269|PubMed:10090481, ECO:0000269|PubMed:10200054, ECO:0000269|PubMed:10208579, ECO:0000269|PubMed:10439444, ECO:0000269|PubMed:10441572, ECO:0000269|PubMed:10447269, ECO:0000269|PubMed:10533070, ECO:0000269|PubMed:10631141, ECO:0000269|PubMed:10644793, ECO:0000269|PubMed:11027672, ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:11710891, ECO:0000269|PubMed:11920851, ECO:0000269|PubMed:12048239, ECO:0000269|PubMed:12484344, ECO:0000269|PubMed:12493737, ECO:0000269|PubMed:20460383, ECO:0000269|PubMed:22503161, ECO:0000269|PubMed:26145164, ECO:0000269|PubMed:26549787, ECO:0000269|PubMed:7550356, ECO:0000269|PubMed:7596406, ECO:0000269|PubMed:7651536, ECO:0000269|PubMed:8634711, ECO:0000269|PubMed:8634712, ECO:0000269|PubMed:8733303, ECO:0000269|PubMed:9172170, ECO:0000269|PubMed:9225696, ECO:0000269|PubMed:9298817, ECO:0000269|PubMed:9384602, ECO:0000269|PubMed:9507958, ECO:0000269|PubMed:9521423, ECO:0000269|PubMed:9719376, ECO:0000269|PubMed:9831473, ECO:0000269|PubMed:9833068, ECO:0000269|Ref.78}. 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 AD3.
Any additional useful information about the variant.

Sequence information

Variant position:  426
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  467
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.

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 299 – 467 Presenilin-1 CTF subunit
Chain 346 – 467 Presenilin-1 CTF12
Transmembrane 408 – 428 Helical
Region 322 – 450 Required for interaction with CTNNB1
Alternative sequence 185 – 467 Missing. In isoform 4.
Mutagenesis 433 – 433 P -> A. No effect on endoproteolytic cleavage. No effect on APP nor NOTCH1 processing. Slightly increased Abeta42/Abeta40 ratio.
Mutagenesis 433 – 433 P -> DFLNV. No endoproteolytic cleavage; no APP nor NOTCH1 processing. No detectable Abetano detectable Abeta.
Mutagenesis 433 – 433 P -> G. Very little endoproteolysis. Little APP processing. No NOTCH1 processing. Very low levels Abeta40 and no detectable Abeta42.
Mutagenesis 434 – 434 A -> C. Some loss of endoproteolytic cleavage. Some loss of APP and NOTCH1 processing. Six-fold increase in Abeta42/Abeta40 ratio.
Mutagenesis 434 – 434 A -> DILV. No endoproteolytic cleavage. No APP nor NOTCH1 processing. No detectable Abeta.
Mutagenesis 434 – 434 A -> G. No effect on endoproteolytic cleavage. No effect on APP nor NOTCH1 processing. Reduced Abeta42/Abeta40 ratio.
Mutagenesis 435 – 435 L -> A. No effect on endoproteolytic cleavage. No effect on APP processing. Impaired NOTCH1 processing. Greatly reduced Abeta42/Abeta40 ratio.
Mutagenesis 435 – 435 L -> G. Greatly reduced endoproteolytic cleavage. Very little APP and NOTCH1 processing. Very low levels of Abeta40 and no detectable Abeta42.
Mutagenesis 435 – 435 L -> I. No effect on endoproteolytic cleavage. No effect on APP nor NOTCH1 processing.
Mutagenesis 435 – 435 L -> V. No effect on endoproteolytic cleavage. No effect on APP processing. Impaired NOTCH1 processing. Some increase in Abeta42/Abeta40 ratio.
Helix 407 – 428

Literature citations

Missense mutations in the chromosome 14 familial Alzheimer's disease presenilin 1 gene.
Poorkaj P.; Sharma V.; Anderson L.; Nemens E.; Alonso M.E.; Orr H.; White J.; Heston L.; Bird T.D.; Schellenberg G.D.;
Hum. Mutat. 11:216-221(1998)
Cited for: VARIANTS AD3 ASP-120; ARG-163; VAL-209; VAL-260; LEU-264; TYR-410 AND PRO-426;

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.