UniProtKB/SwissProt variant VAR

Variant information

Variant position:

436

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 Serine (S) to Phenylalanine (F) at position 436 (S436F, p.Ser436Phe).

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 polar (S) to large size and aromatic (F)

The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:

-2

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:

Spastic paraplegia 4, autosomal dominant (SPG4) [MIM:182601]: A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. {ECO:0000269|PubMed:10610178, ECO:0000269|PubMed:10699187, ECO:0000269|PubMed:11015453, ECO:0000269|PubMed:11039577, ECO:0000269|PubMed:11087788, ECO:0000269|PubMed:11309678, ECO:0000269|PubMed:11809724, ECO:0000269|PubMed:11843700, ECO:0000269|PubMed:11985387, ECO:0000269|PubMed:12124993, ECO:0000269|PubMed:12161613, ECO:0000269|PubMed:12163196, ECO:0000269|PubMed:12202986, ECO:0000269|PubMed:12460147, ECO:0000269|PubMed:12552568, ECO:0000269|PubMed:12939659, ECO:0000269|PubMed:14732620, ECO:0000269|PubMed:15159500, ECO:0000269|PubMed:15210521, ECO:0000269|PubMed:15248095, ECO:0000269|PubMed:15326248, ECO:0000269|PubMed:15482961, ECO:0000269|PubMed:15667412, ECO:0000269|PubMed:15716377, ECO:0000269|PubMed:15891913, ECO:0000269|PubMed:16339213, ECO:0000269|PubMed:16682546, ECO:0000269|PubMed:16684598, ECO:0000269|PubMed:17389232, ECO:0000269|PubMed:17594340, ECO:0000269|PubMed:19000169, ECO:0000269|PubMed:20214791, ECO:0000269|PubMed:20550563, ECO:0000269|PubMed:20562464, ECO:0000269|PubMed:20718791, ECO:0000269|PubMed:20932283, ECO:0000269|PubMed:21546041, ECO:0000269|PubMed:22960362, ECO:0000269|PubMed:23279441, ECO:0000269|PubMed:24824479, ECO:0000269|PubMed:25045380, ECO:0000269|PubMed:25421405, ECO:0000269|PubMed:28572275}. 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 SPG4.

Any additional useful information about the variant.

Sequence information

Variant position:

436

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

Protein sequence length:

616

The length of the canonical sequence.

Location on the sequence:

VGEGEKLVRALFAVARELQP S IIFIDEVDSLLCERREGEHD

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:

The multiple alignment of the region surrounding the variant against various orthologous sequences.

Human                         VGEGEKLVRALFAVARELQPSIIFIDEVDSLLCERREGEHD

Mouse                         VGEGEKLVRALFAVARELQPSIIFIDEVDSLLCERREGEHD

Rat                           VGEGEKLVRALFAVARELQPSIIFIDEVDSLLCERREGEHD

Pig                           VGEGEKLVRALFAVARELQPSIIFIDEVDSLLRERREGEHD

Bovine                        VGEGEKLVRALFAVARELQPSIIFIDEVDSLLCERREGEHD

Chicken                       VGEGEKLVRALFAVARELQPSIIFIDEVDSLLCERREGEHD

Xenopus laevis                VGEGEKLVRALFSVARELQPSIIFIDEVDSLLCERREGEHD

Xenopus tropicalis            VGEGEKLVRALFSVARELQPSIIFIDEVDSLLCERREGEHD

Zebrafish                     VGEGEKLVRALFAVARELQPSIIFIDEIDSLLCERREGEHD

Caenorhabditis elegans        VGDSEKTIRGLFQIARNAQPSIIFIDEIDSILCERSEKDAE

Drosophila                    VGDGEKLVRALFAVARHMQPSIIFIDEVDSLLSERSSSEHE

Slime mold                    VGDGEKLVRALFAVATHFQPSIIFIDEIDSLLTERSSNESE

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	1 – 616	Spastin
Topological domain	78 – 616	Cytoplasmic
Region	228 – 616	Sufficient for microtubule severing
Mutagenesis	442 – 442	E -> Q. Abrogates ATP hydrolysis, abolishes microtubule severing, stabilizes the homohexameric form, and promotes microtubule binding and redistribution from the endosome to microtubules.
Mutagenesis	448 – 448	C -> AG. Abolishes ATPase activity.
Mutagenesis	448 – 448	C -> S. Does not affect ATPase activity.
Mutagenesis	451 – 451	R -> G. Abrogates binding to the tail of alpha-tubulin and beta-3-tubulin, impairs ATPase activity and abolishes microtubule severing.
Beta strand	435 – 442

Literature citations

Novel mutations in spastin gene and absence of correlation with age at onset of symptoms.
Hentati A.; Deng H.-X.; Zhai H.; Chen W.; Yang Y.; Hung W.-Y.; Azim A.C.; Bohlega S.; Tandan R.; Warner C.; Laing N.G.; Cambi F.; Mitsumoto H.; Roos R.P.; Boustany R.-M.N.; Ben-Hamida M.; Hentati F.; Siddique T.;
Neurology 55:1388-1390(2000)
Cited for: VARIANTS SPG4 PHE-436 AND ASP-559;

UniProtKB/Swiss-Prot Q9UBP0: Variant p.Ser436Phe