UniProtKB/Swiss-Prot P55072: Variant p.Arg95Gly

Transitional endoplasmic reticulum ATPase
Gene: VCP
Chromosomal location: 9p12-p13
Variant information

Variant position:  95
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 Arginine (R) to Glycine (G) at position 95 (R95G, p.Arg95Gly).
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 large size and basic (R) to glycine (G)
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:  Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 1 (IBMPFD1) [MIM:167320]: An autosomal dominant disease characterized by disabling muscle weakness clinically resembling to limb girdle muscular dystrophy, osteolytic bone lesions consistent with Paget disease, and premature frontotemporal dementia. Clinical features show incomplete penetrance. {ECO:0000269|PubMed:15034582, ECO:0000269|PubMed:15732117, ECO:0000269|PubMed:16247064, ECO:0000269|PubMed:16321991, ECO:0000269|PubMed:17935506, ECO:0000269|PubMed:20104022, ECO:0000269|PubMed:20335036, ECO:0000269|PubMed:20512113, ECO:0000269|PubMed:21822278, ECO:0000269|PubMed:23349634, ECO:0000269|PubMed:25125609, ECO:0000269|PubMed:25878907, ECO:0000269|PubMed:27209344, ECO:0000269|PubMed:27753622}. 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 IBMPFD1; cultured cells expressing the mutant protein show a marked general increase in the level of ubiquitin-conjugated proteins and impaired protein degradation through the endoplasmic reticulum-associated degradation (ERAD) pathway; shows strongly reduced affinity for ADP and increased affinity for ATP; abolishes enhancement of K-315 methylation by ASPSCR1; decreased interaction with CAV1 and UBXN6.
Any additional useful information about the variant.

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



Sequence information

Variant position:  95
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  806
The length of the canonical sequence.

Location on the sequence:   DTCSDEKIRMNRVVRNNLRV  R LGDVISIQPCPDVKYGKRIH
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                         DTCSDEKIRMNRVVRNNLRVRLGDVISIQPCPDVKYGKRIH

Mouse                         DTCSDEKIRMNRVVRNNLRVRLGDVISIQPCPDVKYGKRIH

Rat                           DTCSDEKIRMNRVVRNNLRVRLGDVISIQPCPDVKYGKRIH

Pig                           DTCSDEKIRMNRVVRNNLRVHLGDVISIQPCPDVKYGKRIH

Bovine                        DTCSDEKIRMNRVVRNNLRVHLGDVISIQPCPDVKYGKRIH

Xenopus laevis                DTCSDEKIRMNRVVRNNLRVRLGDVISIQPCPDVKYGKRVH

Xenopus tropicalis            DTCSDEKIRMNRVVRNNLRVRLGDVISIQPCPDVKYGKRIH

Zebrafish                     DTCSDEKVRMNRVVRNNLRVRLGDVISIQPCPDVKYGKRIH

Drosophila                    DTCPDEKIRMNRVVRNNLCVHLSDVVSVQSCPDVKYGKRVR

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 – 806 Transitional endoplasmic reticulum ATPase
Mutagenesis 86 – 86 R -> A. Strongly increased affinity for ATP. Strongly reduced affinity for ADP.
Mutagenesis 110 – 110 Y -> A. Abolishes interaction with NPLOC4; when associated with 52-A--A-55.
Beta strand 93 – 95


Literature citations

Endolysosomal sorting of ubiquitylated caveolin-1 is regulated by VCP and UBXD1 and impaired by VCP disease mutations.
Ritz D.; Vuk M.; Kirchner P.; Bug M.; Schuetz S.; Hayer A.; Bremer S.; Lusk C.; Baloh R.H.; Lee H.; Glatter T.; Gstaiger M.; Aebersold R.; Weihl C.C.; Meyer H.;
Nat. Cell Biol. 13:1116-1123(2011)
Cited for: FUNCTION; INTERACTION WITH CAV1 AND UBXN6; CHARACTERIZATION OF VARIANTS IBMPFD1 GLY-95; HIS-155 AND GLU-232; MUTAGENESIS OF GLU-578;

A novel ATP-dependent conformation in p97 N-D1 fragment revealed by crystal structures of disease-related mutants.
Tang W.K.; Li D.; Li C.C.; Esser L.; Dai R.; Guo L.; Xia D.;
EMBO J. 29:2217-2229(2010)
Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 1-481 IN COMPLEX WITH ATP ANALOG; CHARACTERIZATION OF VARIANTS IBMPFD1 GLY-95 AND HIS-155; MUTAGENESIS OF ARG-53 AND ARG-86; SUBUNIT;

Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein.
Watts G.D.J.; Wymer J.; Kovach M.J.; Mehta S.G.; Mumm S.; Darvish D.; Pestronk A.; Whyte M.P.; Kimonis V.E.;
Nat. Genet. 36:377-381(2004)
Cited for: VARIANTS IBMPFD1 GLY-95; CYS-155; HIS-155; PRO-155; GLN-191 AND GLU-232;

Inclusion body myopathy-associated mutations in p97/VCP impair endoplasmic reticulum-associated degradation.
Weihl C.C.; Dalal S.; Pestronk A.; Hanson P.I.;
Hum. Mol. Genet. 15:189-199(2006)
Cited for: CHARACTERIZATION OF VARIANTS IBMPFD1 GLY-95 AND HIS-155;

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.