UniProtKB/SwissProt variant VAR

Variant information

Variant position:

250

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 Glutamate (E) to Glutamine (Q) at position 250 (E250Q, p.Glu250Gln).

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 acidic (E) to medium size and polar (Q)

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:

PAPA syndrome (PAPAS) [MIM:604416]: Characterized by autosomal dominant inheritance of early-onset, primarily affecting skin and joint tissues. Recurring inflammatory episodes lead to accumulation of sterile, pyogenic, neutrophil-rich material within the affected joints, ultimately resulting in significant destruction. {ECO:0000269|PubMed:11971877, ECO:0000269|PubMed:14595024, ECO:0000269|PubMed:22161697}. 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 PAPAS; severely reduced binding with PTPN12; markedly increased binding to MEFV; accentuates IL1B secretion; increased induction of MEFV in response to retroviral infection.

Any additional useful information about the variant.

Other resources:

Links to websites of interest for the variant.

Variant rs28939089 [ dbSNP | Ensembl ]

Sequence information

Variant position:

250

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

Protein sequence length:

416

The length of the canonical sequence.

Location on the sequence:

ALWVHSNQLSMQCVKDDELY E EVRLTLEGCSIDADIDSFIQ

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                         ALWVHSNQLSMQCVKDDELYEEVRLTLEGCSIDADIDSFIQ

Mouse                         ALWVHCNQLSMQCVKDDELYEEVRLTLEGCDVEGDINGFIQ

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 – 416	Proline-serine-threonine phosphatase-interacting protein 1
Domain	5 – 264	F-BAR
Mutagenesis	232 – 232	W -> A. Abolishes binding to MEFV. Cytoplasmic filaments are finer with fewer branches.
Mutagenesis	266 – 266	D -> N. No effect on filament formation.

Literature citations

Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway.
Shoham N.G.; Centola M.; Mansfield E.; Hull K.M.; Wood G.; Wise C.A.; Kastner D.L.;
Proc. Natl. Acad. Sci. U.S.A. 100:13501-13506(2003)
Cited for: INTERACTION WITH MEFV; TISSUE SPECIFICITY; CHARACTERIZATION OF VARIANTS PAPAS THR-230 AND GLN-250; MUTAGENESIS OF TRP-232 AND TYR-345;

Pyrin activates the ASC pyroptosome in response to engagement by autoinflammatory PSTPIP1 mutants.
Yu J.W.; Fernandes-Alnemri T.; Datta P.; Wu J.; Juliana C.; Solorzano L.; McCormick M.; Zhang Z.; Alnemri E.S.;
Mol. Cell 28:214-227(2007)
Cited for: FUNCTION; SUBUNIT; INTERACTION WITH MEFV; CHARACTERIZATION OF VARIANTS THR-230 AND GLN-250;

Pyrin Modulates the Intracellular Distribution of PSTPIP1.
Waite A.L.; Schaner P.; Richards N.; Balci-Peynircioglu B.; Masters S.L.; Brydges S.D.; Fox M.; Hong A.; Yilmaz E.; Kastner D.L.; Reinherz E.L.; Gumucio D.L.;
PLoS ONE 4:E6147-E6147(2009)
Cited for: FUNCTION; SUBUNIT; SUBCELLULAR LOCATION; CHARACTERIZATION OF VARIANTS THR-230 AND GLN-250; MUTAGENESIS OF TRP-232 AND ASP-266;

Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder.
Wise C.A.; Gillum J.D.; Seidman C.E.; Lindor N.M.; Veile R.; Bashiardes S.; Lovett M.;
Hum. Mol. Genet. 11:961-969(2002)
Cited for: VARIANTS PAPAS THR-230 AND GLN-250; CHARACTERIZATION OF VARIANTS PAPAS THR-230 AND GLN-250;

Brief report: genotype, phenotype, and clinical course in five patients with PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne).
Demidowich A.P.; Freeman A.F.; Kuhns D.B.; Aksentijevich I.; Gallin J.I.; Turner M.L.; Kastner D.L.; Holland S.M.;
Arthritis Rheum. 64:2022-2027(2012)
Cited for: VARIANTS PAPAS THR-230; GLN-250 AND LYS-250;

UniProtKB/Swiss-Prot variant pages

UniProtKB/Swiss-Prot O43586: Variant p.Glu250Gln