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UniProtKB/Swiss-Prot P49768: Variant p.Val261Phe

Presenilin-1
Gene: PSEN1
Variant information

Variant position:  261
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 Valine (V) to Phenylalanine (F) at position 261 (V261F, p.Val261Phe).
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 hydrophobic (V) to large size and aromatic (F)
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 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: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:11561050, ECO:0000269|PubMed:11568920, ECO:0000269|PubMed:11701593, ECO:0000269|PubMed:11710891, ECO:0000269|PubMed:11796781, ECO:0000269|PubMed:11920851, ECO:0000269|PubMed:12048239, ECO:0000269|PubMed:12058025, ECO:0000269|PubMed:12370477, ECO:0000269|PubMed:12484344, ECO:0000269|PubMed:12493737, ECO:0000269|PubMed:12552037, ECO:0000269|PubMed:15004326, ECO:0000269|PubMed:15122701, ECO:0000269|PubMed:15364419, ECO:0000269|PubMed:15534188, ECO:0000269|PubMed:15534260, ECO:0000269|PubMed:15851849, ECO:0000269|PubMed:16305624, ECO:0000269|PubMed:16344340, ECO:0000269|PubMed:16628450, ECO:0000269|PubMed:16752394, ECO:0000269|PubMed:16897084, ECO:0000269|PubMed:16959576, ECO:0000269|PubMed:17366635, ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:17502474, ECO:0000269|PubMed:18430735, ECO:0000269|PubMed:19667325, ECO:0000269|PubMed:19797784, ECO:0000269|PubMed:20164095, ECO:0000269|PubMed:20460383, ECO:0000269|PubMed:21335660, ECO:0000269|PubMed:21501661, ECO:0000269|PubMed:22461631, ECO:0000269|PubMed:22503161, ECO:0000269|PubMed:22529981, ECO:0000269|PubMed:23123781, ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:24121961, ECO:0000269|PubMed:24495933, ECO:0000269|PubMed:24582897, ECO:0000269|PubMed:25394380, ECO:0000269|PubMed:26145164, ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:26549787, ECO:0000269|PubMed:27073747, ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:29175279, ECO:0000269|PubMed:29404783, ECO:0000269|PubMed:29466804, ECO:0000269|PubMed:30180983, ECO:0000269|PubMed:30200536, 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:8837617, 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.92}. 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; nearly abolishes protease activity with APP; increased amyloid-beta 42/amyloid-beta 40 ratio.
Any additional useful information about the variant.

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



Sequence information

Variant position:  261
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  467
The length of the canonical sequence.

Location on the sequence:   LPEWTAWLILAVISVYDLVA  V LCPKGPLRMLVETAQERNET
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.

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

An atomic structure of human gamma-secretase.
Bai X.C.; Yan C.; Yang G.; Lu P.; Ma D.; Sun L.; Zhou R.; Scheres S.H.; Shi Y.;
Nature 525:212-217(2015)
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS); SUBCELLULAR LOCATION; TOPOLOGY; SUBUNIT; FUNCTION; CATALYTIC ACTIVITY; CHARACTERIZATION OF VARIANTS AD3 LEU-213; ILE-237 AND PHE-261; MUTAGENESIS OF ILE-202; LEU-226; LEU-248 AND LEU-424;

Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations.
Rogaeva E.A.; Fafel K.C.; Song Y.Q.; Medeiros H.; Sato C.; Liang Y.; Richard E.; Rogaev E.I.; Frommelt P.; Sadovnick A.D.; Meschino W.; Rockwood K.; Boss M.A.; Mayeux R.; St George-Hyslop P.;
Neurology 57:621-625(2001)
Cited for: VARIANTS AD3 GLN-35; VAL-79; CYS-115; ASN-116; THR-143; ILE-146; LEU-146; VAL-146; TYR-156 DELINS PHE-THR-TYR; ARG-163; LEU-177; SER-177; PRO-178; ALA-206; SER-206; GLU-209; LEU-213; ARG-222; THR-231; LEU-233; PRO-235; PHE-261; ARG-274; ARG-352 INS; ILE-354; GLN-358; TYR-365; VAL-394; PHE-418; GLU-431; PHE-435 AND VAL-439; VARIANT GLY-318;

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.