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UniProtKB/Swiss-Prot variant pages

UniProtKB/Swiss-Prot P02649: Variant p.Arg176Cys

Apolipoprotein E
Gene: APOE
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Variant information Variant position: help 176 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 Arginine (R) to Cysteine (C) at position 176 (R176C, p.Arg176Cys). 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 large size and basic (R) to medium size and polar (C) The physico-chemical property of the reference and variant residues and the change implicated.
BLOSUM score: help -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: help In HLPP3; ApoE2, ApoE2 Fukuoka, ApoE1 Weisgraber and ApoE3**; ApoE3** is associated with HLPP3; changed protein structure; decreased binding to LDLR and other lipoprotein receptors; decreased in vitro binding to heparin; no effect on distribution among plasma lipoproteins. Any additional useful information about the variant.
Other resources: help Links to websites of interest for the variant.


Sequence information Variant position: help 176 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length: help 317 The length of the canonical sequence.
Location on the sequence: help ASHLRKLRKRLLRDADDLQK R LAVYQAGAREGAERGLSAIR 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: help The multiple alignment of the region surrounding the variant against various orthologous sequences.
Human                         ASHLRKLRKRLLRDADDLQKRLAVYQAGAREGAERGLSAIR

Gorilla                       ASHLRKLRKRLLRDADDLQKRLAVYQAGAREGAERGVSAIR

                              ASHMRKLRKRVLRDAEDLQRRLAVYKAGVREGAERSVSSIR

Rhesus macaque                ASHLRKLRKRLLRDADDLQKRLA------------------

Chimpanzee                    ASHLRKLRKRLLRDADDLQKRLAVYQAGAREGAERGVSAIR

Mouse                         STHLRKMRKRLMRDAEDLQKRLAVYKAGAREGAERGVSAIR

Rat                           STHLRKMRKRLMRDADDLQKRLAVYKAGAQEGAERGVSAIR

Pig                           ASHLRNVRKRLVRDTEDLQKRLAVYQAGLREGAERSVSALR

Bovine                        ASHLRKLPKRLLRDADDLKKRLAVYQAGASEGAERSLSAIR

Rabbit                        SSHLRKLRKRLLRDAEDLQKRMAVYGAGAREGAERGVSAVR

Sheep                         ASHLRKLRKRLLRDADDLKKRLAVYQAGASEGAERSVSAIR

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 19 – 317 Apolipoprotein E
Repeat 168 – 189 5
Region 80 – 255 8 X 22 AA approximate tandem repeats
Mutagenesis 157 – 157 S -> R. Increased binding to LDL receptor; when associated with A-167.
Mutagenesis 158 – 158 H -> A. Decreased binding to LDL receptor.
Mutagenesis 161 – 161 K -> A. Decreased binding to LDL receptor.
Mutagenesis 162 – 162 L -> P. Decreased binding to LDL receptor.
Mutagenesis 167 – 167 L -> A. Increased binding to LDL receptor; when associated with R-157.
Mutagenesis 168 – 168 R -> A. Decreased binding to LDL receptor.
Mutagenesis 172 – 172 D -> A. Restores the LDL receptor binding activity of ApoE2.
Helix 149 – 180



Literature citations
Genotyping and sequence analysis of apolipoprotein E isoforms.
Emi M.; Wu L.L.; Robertson M.A.; Myers R.L.; Hegele R.A.; Williams R.R.; White R.; Lalouel J.-M.;
Genomics 3:373-379(1988)
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ALLELE APOE*2); VARIANT CYS-176; Sequence diversity and large-scale typing of SNPs in the human apolipoprotein E gene.
Nickerson D.A.; Taylor S.L.; Fullerton S.M.; Weiss K.M.; Clark A.G.; Stengard J.H.; Salomaa V.; Boerwinkle E.; Sing C.F.;
Genome Res. 10:1532-1545(2000)
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ALLELE APOE*3); VARIANTS PRO-46; ARG-130; CYS-163 AND CYS-176; Domains of apoE required for binding to apoE receptor 2 and to phospholipids: implications for the functions of apoE in the brain.
Li X.; Kypreos K.; Zanni E.E.; Zannis V.;
Biochemistry 42:10406-10417(2003)
Cited for: FUNCTION; LRP8-BINDING; CHARACTERIZATION OF VARIANT CYS-176; Salt bridge relay triggers defective LDL receptor binding by a mutant apolipoprotein.
Wilson C.; Mau T.; Weisgraber K.H.; Wardell M.R.; Mahley R.W.; Agard D.A.;
Structure 2:713-718(1994)
Cited for: X-RAY CRYSTALLOGRAPHY (3.00 ANGSTROMS) OF 41-184 OF VARIANT CYS-176; CHARACTERIZATION OF VARIANT CYS-176; Novel mechanism for defective receptor binding of apolipoprotein E2 in type III hyperlipoproteinemia.
Dong L.-M.; Parkin S.; Trakhanov S.D.; Rupp B.; Simmons T.; Arnold K.S.; Newhouse Y.M.; Innerarity T.L.; Weisgraber K.H.;
Nat. Struct. Biol. 3:718-722(1996)
Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 19-209 OF VARIANT CYS-176; MUTAGENESIS OF ASP-172; CHARACTERIZATION OF VARIANT CYS-176; FUNCTION; LDLR-BINDING; Common and rare genotypes of human apolipoprotein E determined by specific restriction profiles of polymerase chain reaction-amplified DNA.
Richard P.; Thomas G.; de Zulueta M.P.; de Gennes J.-L.; Thomas M.; Cassaigne A.; Bereziat G.; Iron A.;
Clin. Chem. 40:24-29(1994)
Cited for: VARIANTS HLPP3 ARG-130; SER-154; CYS-160 AND CYS-176; VARIANT ASP-145; Dominant expression of type III hyperlipoproteinemia. Pathophysiological insights derived from the structural and kinetic characteristics of ApoE-1 (Lys146-->Glu).
Mann W.A.; Lohse P.; Gregg R.E.; Ronan R.; Hoeg J.M.; Zech L.A.; Brewer H.B. Jr.;
J. Clin. Invest. 96:1100-1107(1995)
Cited for: VARIANT HLPP3 GLU-164; CHARACTERIZATION OF VARIANT HLPP3 GLU-164 AND CYS-176; FUNCTION; LDLR-BINDING; HEPARIN-BINDING; Association of extreme blood lipid profile phenotypic variation with 11 reverse cholesterol transport genes and 10 non-genetic cardiovascular disease risk factors.
Morabia A.; Cayanis E.; Costanza M.C.; Ross B.M.; Flaherty M.S.; Alvin G.B.; Das K.; Gilliam T.C.;
Hum. Mol. Genet. 12:2733-2743(2003)
Cited for: VARIANTS ARG-130 AND CYS-176;
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.