UniProtKB/Swiss-Prot P00441: Variant p.Ala5Val

• Variant information
• Sequence information
• Literature citations
• All

Variant information

Variant position: 5 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 Alanine (A) to Valine (V) at position 5 (A5V, p.Ala5Val). 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 (V) The physico-chemical property of the reference and variant residues and the change implicated.
BLOSUM score: 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: In ALS1; severe form; reduces structural stability and enzyme activity; increases tendency to form fibrillar aggregates. Any additional useful information about the variant.
Other resources: Links to websites of interest for the variant.

• Variant rs121912442 [ dbSNP | Ensembl ]

Sequence information

Variant position: 5 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length: 154 The length of the canonical sequence.
Location on the sequence: MATK A VCVLKGDGPVQGIINFEQKE 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
Initiator methionine	1 – 1	Removed
Chain	2 – 154	Superoxide dismutase [Cu-Zn]
Modified residue	2 – 2	N-acetylalanine
Modified residue	4 – 4	N6-succinyllysine
Modified residue	10 – 10	N6-succinyllysine
Lipidation	7 – 7	S-palmitoyl cysteine
Mutagenesis	7 – 7	C -> S. Enhances formation of fibrillar aggregates in the absence of bound zinc; when associated with S-58; S-112 and S-147.
Mutagenesis	7 – 7	C -> S. No palmitoylation, reduced nuclear targeting.
Beta strand	3 – 10

Literature citations

ALS mutants of human superoxide dismutase form fibrous aggregates via framework destabilization.
DiDonato M.; Craig L.; Huff M.E.; Thayer M.M.; Cardoso R.M.; Kassmann C.J.; Lo T.P.; Bruns C.K.; Powers E.T.; Kelly J.W.; Getzoff E.D.; Tainer J.A.;
J. Mol. Biol. 332:601-615(2003)
Cited for: X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) IN COMPLEX WITH COPPER AND ZINC IONS; DISULFIDE BOND; SUBUNIT; CHARACTERIZATION OF VARIANTS ALS1 VAL-5 AND ARG-44; Dimer destabilization in superoxide dismutase may result in disease-causing properties: structures of motor neuron disease mutants.
Hough M.A.; Grossmann J.G.; Antonyuk S.V.; Strange R.W.; Doucette P.A.; Rodriguez J.A.; Whitson L.J.; Hart P.J.; Hayward L.J.; Valentine J.S.; Hasnain S.S.;
Proc. Natl. Acad. Sci. U.S.A. 101:5976-5981(2004)
Cited for: X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF VARIANTS ALS1 VAL-5 AND THR-114; CHARACTERIZATION OF VARIANTS ALS1 VAL-5 AND THR-114; Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase.
Deng H.-X.; Hentati A.; Tainer J.A.; Iqbal Z.; Cayabyab A.; Hung W.-Y.; Getzoff E.D.; Hu P.; Herzfeldt B.; Roos R.P.; Warner C.; Deng G.; Soriano E.; Smyth C.; Parge H.E.; Ahmed A.; Roses A.D.; Hallewell R.A.; Pericak-Vance M.A.; Siddique T.;
Science 261:1047-1051(1993)
Cited for: VARIANTS ALS1 VAL-5; ARG-38; VAL-39; ASP-42; SER-42; ARG-44; ARG-86; ALA-94; CYS-94; GLY-101; VAL-107; THR-114; PHE-145 AND GLY-149; Identification of new mutations in the Cu/Zn superoxide dismutase gene of patients with familial amyotrophic lateral sclerosis.
Pramatarova A.; Figlewicz D.A.; Krizus A.; Han F.Y.; Ceballos-Picot I.; Nicole A.; Dib M.; Meininger V.; Brown R.H. Jr.; Rouleau G.A.;
Am. J. Hum. Genet. 56:592-596(1995)
Cited for: VARIANTS ALS1 VAL-5; ARG-38; THR-114; LYS-140; PHE-145 AND THR-150; Phenotypic heterogeneity in motor neuron disease patients with CuZn-superoxide dismutase mutations in Scandinavia.
Andersen P.M.; Nilsson P.; Keraenen M.L.; Forsgren L.; Haegglund J.; Karlsborg M.; Ronnevi L.O.; Gredal O.; Marklund S.L.;
Brain 120:1723-1737(1997)
Cited for: VARIANTS ALS1 VAL-5; GLY-15; TYR-77 AND ALA-91; Variation in the biochemical/biophysical properties of mutant superoxide dismutase 1 enzymes and the rate of disease progression in familial amyotrophic lateral sclerosis kindreds.
Ratovitski T.; Corson L.B.; Strain J.; Wong P.; Cleveland D.W.; Culotta V.C.; Borchelt D.R.;
Hum. Mol. Genet. 8:1451-1460(1999)
Cited for: CHARACTERIZATION OF VARIANTS ALS1 VAL-5; ARG-38; ARG-47; GLN-49; ARG-86 AND THR-114;