UniProtKB/Swiss-Prot P35568: Variant p.Ala512Pro

Insulin receptor substrate 1
Gene: IRS1
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Variant information Variant position:

512 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Type of variant:

LB/B The variants are classified into three categories: LP/P, LB/B and US.

LP/P: likely pathogenic or pathogenic.
LB/B: likely benign or benign.
US: uncertain significance

Residue change:

From Alanine (A) to Proline (P) at position 512 (A512P, p.Ala512Pro). 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 hydrophobic (A) to medium size and hydrophobic (P) 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
Polymorphism:

The Arg-971 polymorphism impairs the ability of insulin to stimulate glucose transport, glucose transporter translocation, and glycogen synthesis by affecting the PI3K/AKT1/GSK3 signaling pathway. The polymorphism at Arg-971 may contribute to the in vivo insulin resistance observed in carriers of this variant. Arg-971 could contribute to the risk for atherosclerotic cardiovascular diseases associated with non-insulin-dependent diabetes mellitus (NIDDM) by producing a cluster of insulin resistance-related metabolic abnormalities. In insulin-stimulated human endothelial cells from carriers of the Arg-971 polymorphism, genetic impairment of the IRS1/PI3K/PDPK1/AKT1 insulin signaling cascade results in impaired insulin-stimulated nitric oxide (NO) release and suggested that this may be a mechanism through which the Arg-971 polymorphism contributes to the genetic predisposition to develop endothelial dysfunction and cardiovascular disease. The Arg-971 polymorphism not only reduces phosphorylation of the substrate but allows IRS1 to act as an inhibitor of PI3K, producing global insulin resistance. Additional information on the polymorphism described.
Other resources:

Links to websites of interest for the variant.

Variant rs1801276 [ dbSNP | Ensembl ]

Sequence information Variant position:

512 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length:

1242 The length of the canonical sequence.
Location on the sequence:

HRCTPGTGLGTSPALAGDEA A SAADLDNRFRKRTHSAGTSP 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                         HRCTPGTGLGTSPALAGDEAASAADL--DNRFRKRTHSAGTSP

Mouse                         HRYIPGANLGTSPALPGDEAAGAADL--DNRFRKRTHSAGT

Rat                           HRYIPGATMGTSPALTGDEAAGAADL--DNRFRKRTHSAGT

Xenopus tropicalis            ----------------------------------------M

Drosophila                    SLHF------NFPEHASEKLAKDFDLDSDNQCCRPIRAYSI

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 – 1242	Insulin receptor substrate 1
Modified residue	527 – 527	Phosphoserine; by RPS6KB1
Mutagenesis	527 – 527	S -> A. Impaired degradation by the Cul7-RING(FBXW8) complex; when associated with A-307; A-312; A-636 and A-639.

Literature citations
Aminoacid polymorphisms of insulin receptor substrate-1 in non-insulin-dependent diabetes mellitus.
Almind K.; Bjoerbaek C.; Vestergaard H.; Hansen T.; Echwald S.; Pedersen O.;
Lancet 342:828-832(1993)
Cited for: VARIANTS PRO-512 AND ARG-971;

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.