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UniProtKB/Swiss-Prot Q9UHD9: Variant p.Pro497His

Ubiquilin-2
Gene: UBQLN2
Variant information

Variant position:  497
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 Histidine (H) at position 497 (P497H, p.Pro497His).
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 medium size and polar (H)
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:  Amyotrophic lateral sclerosis 15, with or without frontotemporal dementia (ALS15) [MIM:300857]: 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. Patients with ALS15 may develop frontotemporal dementia. {ECO:0000269|PubMed:21857683, ECO:0000269|PubMed:22560112, ECO:0000269|PubMed:22717235, ECO:0000269|PubMed:22892309, ECO:0000269|PubMed:24215460, ECO:0000269|PubMed:25616961}. 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 ALS15; leads to defective ubiquitin-mediated proteasomal degradation; reduces binding to HNRNPA1 and FAF2; increases translocation of HNRNPA1 to the cytoplasm; adversely affects ERAD.
Any additional useful information about the variant.

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



Sequence information

Variant position:  497
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  624
The length of the canonical sequence.

Location on the sequence:   TPGVGVGVLGTAIGPVGPVT  P IGPIGPIVPFTPIGPIGPIG
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                         TPGVGVGVLGTAIGPVGPVTPIGPIGPIVPFTPIGPIGPIG

Mouse                         APGVGMGVLGTAITPVGPVTPIGPIGPIVPFTPIGPIGPIG

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 – 624 Ubiquilin-2
Repeat 497 – 499 3
Region 491 – 526 12 X 3 AA tandem repeats of P-X-X


Literature citations

Pathogenic mutation of UBQLN2 impairs its interaction with UBXD8 and disrupts endoplasmic reticulum-associated protein degradation.
Xia Y.; Yan L.H.; Huang B.; Liu M.; Liu X.; Huang C.;
J. Neurochem. 129:99-106(2014)
Cited for: FUNCTION; INTERACTION WITH FAF2; CHARACTERIZATION OF VARIANT ALS15 HIS-497;

Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia.
Deng H.X.; Chen W.; Hong S.T.; Boycott K.M.; Gorrie G.H.; Siddique N.; Yang Y.; Fecto F.; Shi Y.; Zhai H.; Jiang H.; Hirano M.; Rampersaud E.; Jansen G.H.; Donkervoort S.; Bigio E.H.; Brooks B.R.; Ajroud K.; Sufit R.L.; Haines J.L.; Mugnaini E.; Pericak-Vance M.A.; Siddique T.;
Nature 477:211-215(2011)
Cited for: VARIANTS ALS15 HIS-497; SER-497; THR-506; SER-509 AND SER-525; CHARACTERIZATION OF VARIANTS ALS15 HIS-497 AND THR-506;

ALS-linked mutations in ubiquilin-2 or hnRNPA1 reduce interaction between ubiquilin-2 and hnRNPA1.
Gilpin K.M.; Chang L.; Monteiro M.J.;
Hum. Mol. Genet. 24:2565-2577(2015)
Cited for: INTERACTION WITH HNRNPA1 AND HNRNPU; CHARACTERIZATION OF VARIANTS ALS15 HIS-497; SER-497; THR-506; SER-509 AND SER-525;

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.