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UniProtKB/Swiss-Prot O95292: Variant p.Pro56Ser

Vesicle-associated membrane protein-associated protein B/C
Gene: VAPB
Variant information

Variant position:  56
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 Proline (P) to Serine (S) at position 56 (P56S, p.Pro56Ser).
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 (P) to small size and polar (S)
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:  Amyotrophic lateral sclerosis 8 (ALS8) [MIM:608627]: A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. {ECO:0000269|PubMed:15372378, ECO:0000269|PubMed:16891305, ECO:0000269|PubMed:20940299, ECO:0000269|PubMed:22131369}. 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.

Involvement in disease:  Spinal muscular atrophy, proximal, adult, autosomal dominant (SMAPAD) [MIM:182980]: A form of spinal muscular atrophy, a neuromuscular disorder characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy. SMAPAD is characterized by proximal muscle weakness that begins in the lower limbs and then progresses to upper limbs, onset in late adulthood (after third decade) and a benign course. Most of the patients remain ambulatory 10 to 40 years after clinical onset. {ECO:0000269|PubMed:15372378}. 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 ALS8 and SMAPAD; it forms insoluble cytosolic aggregates; cannot activate the UPR pathway; affects interaction with RMDN3; affects cellular calcium homeostasis; induces mislocalization to the non-ER compartments; enhances homodimerization.
Any additional useful information about the variant.

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



Sequence information

Variant position:  56
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  243
The length of the canonical sequence.

Location on the sequence:   TDRNVCFKVKTTAPRRYCVR  P NSGIIDAGASINVSVMLQPF
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                         TDRNVCFKVKTTAPRRYCVRPNSGIIDAGASINVSVMLQPF

Mouse                         TDRNVCFKVKTTVPRRYCVRPNSGVIDAGASLNVSVMLQPF

Rat                           TDRNVCFKVKTTAPRRYCVRPNSGVIDAGASLNVSVMLQPF

Pig                           TDRNVCFKVKTTAPRRYCVRPNSGIIDAGASINVSVMLQPF

Bovine                        TDRNVCFKVKTTAPRRYCVRPNSGIIDAGASINVSVMLQPF

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 2 – 243 Vesicle-associated membrane protein-associated protein B/C
Topological domain 2 – 222 Cytoplasmic
Domain 7 – 124 MSP
Beta strand 52 – 61


Literature citations

Characterization of amyotrophic lateral sclerosis-linked P56S mutation of vesicle-associated membrane protein-associated protein B (VAPB/ALS8).
Kanekura K.; Nishimoto I.; Aiso S.; Matsuoka M.;
J. Biol. Chem. 281:30223-30233(2006)
Cited for: FUNCTION IN ENDOPLASMIC RETICULUM UNFOLDED PROTEIN RESPONSE; CHARACTERIZATION OF VARIANT ALS8 SER-56;

Characterization of the properties of a novel mutation in VAPB in familial amyotrophic lateral sclerosis.
Chen H.J.; Anagnostou G.; Chai A.; Withers J.; Morris A.; Adhikaree J.; Pennetta G.; de Belleroche J.S.;
J. Biol. Chem. 285:40266-40281(2010)
Cited for: FUNCTION IN ENDOPLASMIC RETICULUM UNFOLDED PROTEIN RESPONSE; VARIANT ALS8 ILE-46; CHARACTERIZATION OF VARIANTS ALS8 ILE-46 AND SER-56; SUBUNIT; INTERACTION WITH VAPA; VAMP1 AND VAMP2;

VAPB interacts with the mitochondrial protein PTPIP51 to regulate calcium homeostasis.
De Vos K.J.; Morotz G.M.; Stoica R.; Tudor E.L.; Lau K.F.; Ackerley S.; Warley A.; Shaw C.E.; Miller C.C.;
Hum. Mol. Genet. 21:1299-1311(2012)
Cited for: FUNCTION IN CELLULAR CALCIUM HOMEOSTASIS REGULATION; SUBCELLULAR LOCATION; INTERACTION WITH RMDN3; CHARACTERIZATION OF VARIANT ALS8 SER-56;

A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis.
Nishimura A.L.; Mitne-Neto M.; Silva H.C.; Richieri-Costa A.; Middleton S.; Cascio D.; Kok F.; Oliveira J.R.; Gillingwater T.; Webb J.; Skehel P.; Zatz M.;
Am. J. Hum. Genet. 75:822-831(2004)
Cited for: VARIANT ALS8 SER-56; VARIANT SMAPAD SER-56;

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.