UniProtKB/Swiss-Prot P49768: Variant p.Asp333Gly

• Variant information
• Sequence information
• Literature citations
• All

Variant information

Variant position: 333 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Type of variant: LP/P [Disclaimer: Variants classification is intended for research purposes only, not for clinical and diagnostic use. The label disease variant is assigned according to literature reports on probable disease-association that can be based on theoretical reasons. This label must not be considered as a definitive proof for the pathogenic role of a variant.] 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 Aspartate (D) to Glycine (G) at position 333 (D333G, p.Asp333Gly). 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 acidic (D) to glycine (G) 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
Variant description: In CMD1U; results in slightly decreased protease activity with APP and slightly decreased amyloid-beta 42/amyloid-beta 40 ratio. Any additional useful information about the variant.
Other resources: Links to websites of interest for the variant.

• Variant rs121917809 [ dbSNP | Ensembl ]

Sequence information

Variant position: 333 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: SKYNAESTERESQDTVAEND D GGFSEEWEAQRDSHLGPHRS 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.

Type	Positions	Description
Chain	299 – 467	Presenilin-1 CTF subunit
Topological domain	273 – 380	Cytoplasmic
Region	305 – 333	Disordered
Region	322 – 450	Required for interaction with CTNNB1
Modified residue	346 – 346	Phosphoserine; by PKC
Alternative sequence	185 – 467	Missing. In isoform 4.
Alternative sequence	319 – 467	STERESQDTVAENDDGGFSEEWEAQRDSHLGPHRSTPESRAAVQELSSSILAGEDPEERGVKLGLGDFIFYSVLVGKASATASGDWNTTIACFVAILIGLCLTLLLLAIFKKALPALPISITFGLVFYFATDYLVQPFMDQLAFHQFYI -> RACLPPAAINLLSIAPMAPRLFMPKGACRPTAQKGSHKTLLQRMMMAGSVRNGKPRGTVI. In isoform 3 and isoform 5.
Alternative sequence	319 – 376	Missing. In isoform 6.
Mutagenesis	345 – 345	D -> N. Abolishes caspase cleavage.
Mutagenesis	346 – 346	S -> A. Abolishes PKC-mediated phosphorylation; no effect on PKA-mediated phosphorylation.
Mutagenesis	346 – 346	S -> E. Inhibits caspase-mediated cleavage. Modulates progression of apoptosis.
Mutagenesis	352 – 352	R -> C. Decreased protease activity with APP.

Literature citations

Mutations of presenilin genes in dilated cardiomyopathy and heart failure.
Li D.; Parks S.B.; Kushner J.D.; Nauman D.; Burgess D.; Ludwigsen S.; Partain J.; Nixon R.R.; Allen C.N.; Irwin R.P.; Jakobs P.M.; Litt M.; Hershberger R.E.;
Am. J. Hum. Genet. 79:1030-1039(2006)
Cited for: VARIANT CMD1U GLY-333; 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;