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UniProtKB/Swiss-Prot variant pages

UniProtKB/Swiss-Prot P49768: Variant p.Ala260Val

Presenilin-1
Gene: PSEN1
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Variant information Variant position: help 260 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Type of variant: help 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: help From Alanine (A) to Valine (V) at position 260 (A260V, p.Ala260Val). 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: help Change from small size and hydrophobic (A) to medium size and hydrophobic (V) The physico-chemical property of the reference and variant residues and the change implicated.
BLOSUM score: help 0 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: help In AD3; nearly abolishes protease activity with APP; increased amyloid-beta 42/amyloid-beta 40 ratio; impaired ability to cleave Ephb2/CTF1. Any additional useful information about the variant.
Other resources: help Links to websites of interest for the variant.


Sequence information Variant position: help 260 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length: help 467 The length of the canonical sequence.
Location on the sequence: help YLPEWTAWLILAVISVYDLV A VLCPKGPLRMLVETAQERNE 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: help 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 1 – 298 Presenilin-1 NTF subunit
Transmembrane 249 – 272 Helical
Active site 257 – 257
Alternative sequence 185 – 467 Missing. In isoform 4.
Alternative sequence 257 – 289 Missing. In isoform 7.
Mutagenesis 245 – 245 T -> P. Abolishes protease activity with APP.
Mutagenesis 248 – 248 L -> R. Nearly abolishes protease activity with APP. Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro.
Mutagenesis 256 – 256 Y -> F. Alters gamma-secretase cleavage specificity. Increased production of amyloid-beta protein 42. No effect on enzymatic activity.
Mutagenesis 256 – 256 Y -> S. Nearly abolishes protease activity with APP. Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro.
Mutagenesis 257 – 257 D -> A. Impaired ability to cleave Ephb2/CTF1.
Mutagenesis 257 – 257 D -> A. Loss of endoproteolytic cleavage. Severe decrease of protease activity with APP. Reduces production of amyloid-beta. Reduces production of NICD in NOTCH1 processing.
Mutagenesis 257 – 257 D -> E. Abolishes gamma-secretase activity. Reduces production of amyloid-beta in APP processing. Accumulation of full-length PS1. Loss of binding of transition state analog gamma-secretase inhibitor.
Mutagenesis 272 – 272 V -> A. Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro.
Mutagenesis 273 – 273 E -> A. Decreased protease activity with APP. Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro.
Mutagenesis 278 – 278 R -> K. Nearly abolishes protease activity with APP. Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro.
Helix 243 – 262



Literature citations
Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene.
Rogaev E.I.; Sherrington R.; Rogaeva E.A.; Levesque G.; Ikeda M.; Liang Y.; Chi H.; Lin C.; Holman K.; Tsuda T.; Mar L.; Sorbi S.; Nacmias B.; Piacentini S.; Amaducci L.; Chumakov I.; Cohen D.; Lannfelt L.; Fraser P.E.; Rommens J.M.; St George-Hyslop P.H.;
Nature 376:775-778(1995)
Cited for: VARIANTS AD3 VAL-260; VAL-285 AND VAL-392; 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; Early onset familial Alzheimer's disease: Mutation frequency in 31 families.
Janssen J.C.; Beck J.A.; Campbell T.A.; Dickinson A.; Fox N.C.; Harvey R.J.; Houlden H.; Rossor M.N.; Collinge J.;
Neurology 60:235-239(2003)
Cited for: VARIANTS AD3 CYS-115; ILE-146; VAL-153; CYS-154; ILE-168 DEL; PRO-171; ASP-184; PHE-229; VAL-235; LEU-237; VAL-260; PHE-263; HIS-269; MET-377 AND VAL-378; VARIANT GLY-318; Ligand binding and calcium influx induce distinct ectodomain/gamma-secretase-processing pathways of EphB2 receptor.
Litterst C.; Georgakopoulos A.; Shioi J.; Ghersi E.; Wisniewski T.; Wang R.; Ludwig A.; Robakis N.K.;
J. Biol. Chem. 282:16155-16163(2007)
Cited for: CHARACTERIZATION OF VARIANTS AD3 LEU-117; LEU-146; GLU-246; VAL-260; LEU-264 AND GLY-280; FUNCTION; MUTAGENESIS OF ASP-257; Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Abeta42 and Abeta40 peptides by gamma-secretase.
Sun L.; Zhou R.; Yang G.; Shi Y.;
Proc. Natl. Acad. Sci. U.S.A. 114:E476-E485(2017)
Cited for: CHARACTERIZATION OF VARIANTS AD3 GLN-35; VAL-79; LEU-82; PRO-85; LEU-89; SER-92; MET-94; PHE-96; LEU-97; HIS-115; ASN-116; ASP-120; LYS-120; ARG-134; ASP-135; VAL-139; THR-143; LEU-146; ILE-147; VAL-153; ASN-154; ARG-163; TYR-163; PRO-166; PRO-169; PHE-170; PRO-171; TRP-173; MET-174; LEU-177; PRO-178; VAL-183; ASP-184; ALA-206; SER-206; ARG-209; VAL-209; LEU-213; ARG-217; ARG-222; PHE-229; THR-231; LEU-233; THR-233; ARG-235; PRO-235; VAL-235; ILE-237; GLU-246; SER-250; VAL-260; PHE-261; PHE-262; ARG-263; LEU-264; SER-266; SER-267; GLY-269; VAL-271; ARG-274; VAL-275; ALA-280; GLY-280; ARG-282; VAL-285; VAL-286; ILE-354; GLN-358; GLU-378; VAL-378; VAL-381; ALA-384; ILE-390; VAL-392; VAL-394; THR-396; SER-405; THR-409; TYR-410; PHE-418; PRO-426; GLU-431; PHE-435; SER-436 AND VAL-439; CHARACTERIZATION OF VARIANT CMD1U GLY-333; MUTAGENESIS OF THR-99; PHE-105; ARG-108; LEU-113; PRO-117; GLU-123; HIS-131; ALA-136; ILE-143; LEU-150; TRP-165; ILE-168; PHE-176; GLU-184; ILE-202; SER-212; HIS-214; LEU-219; GLN-223; LEU-226; SER-230; ILE-238; LYS-239; THR-245; LEU-248; TYR-256; VAL-272; GLU-273; ARG-278; PRO-284; THR-291; ARG-352; SER-365; ARG-377; PHE-386; VAL-391; VAL-412; LEU-420; LEU-424; ALA-434 AND ILE-437;
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.