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UniProtKB/Swiss-Prot variant pages

UniProtKB/Swiss-Prot P19525: Variant p.Ser461Cys

Interferon-induced, double-stranded RNA-activated protein kinase
Gene: EIF2AK2
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Variant information Variant position: help 461 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Type of variant: help US 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: help From Serine (S) to Cysteine (C) at position 461 (S461C, p.Ser461Cys). 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: help Change from small size and polar (S) to medium size and polar (C) The physico-chemical property of the reference and variant residues and the change implicated.
BLOSUM score: help -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

Variant description: help In LEUDEN; uncertain significance; reduced phosphorylation of eukaryotic translation initiation factor 2-alpha in patient cells. Any additional useful information about the variant.


Sequence information Variant position: help 461 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length: help 551 The length of the canonical sequence.
Location on the sequence: help NDGKRTRSKGTLRYMSPEQI S SQDYGKEVDLYALGLILAEL 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: help The multiple alignment of the region surrounding the variant against various orthologous sequences.
Human                         NDGK----------------RTRSKGTLRYMSPE--Q-ISSQD--YGKEVDLYALGLILAEL

Mouse                         NDGKS---------------RTRRTGTLQYMSPE--Q-LFL

Rat                           NDGNP---------------RTKYTGTPQYMSPE--QKSSL

Fission yeast                 KNTETALSFLERNHLPNLQDETQHIGTATYAAPELLDAMSS

Sequence annotation in neighborhood: help 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 – 551 Interferon-induced, double-stranded RNA-activated protein kinase
Domain 267 – 538 Protein kinase
Region 266 – 551 Interaction with TRAF5
Region 379 – 496 Interaction with EIF2S1/EIF-2ALPHA
Modified residue 446 – 446 Phosphothreonine; by autocatalysis
Modified residue 451 – 451 Phosphothreonine; by autocatalysis
Modified residue 456 – 456 Phosphoserine
Mutagenesis 446 – 446 T -> A. Significant loss of activity and impairs autophosphorylation of T-451.
Mutagenesis 451 – 451 T -> A. Loss of activity.
Helix 457 – 461



Literature citations
De novo EIF2AK1 and EIF2AK2 variants are associated with developmental delay, leukoencephalopathy, and neurologic decompensation.
Mao D.; Reuter C.M.; Ruzhnikov M.R.Z.; Beck A.E.; Farrow E.G.; Emrick L.T.; Rosenfeld J.A.; Mackenzie K.M.; Robak L.; Wheeler M.T.; Burrage L.C.; Jain M.; Liu P.; Calame D.; Kuery S.; Sillesen M.; Schmitz-Abe K.; Tonduti D.; Spaccini L.; Iascone M.; Genetti C.A.; Koenig M.K.; Graf M.; Tran A.; Alejandro M.; Lee B.H.; Thiffault I.; Agrawal P.B.; Bernstein J.A.; Bellen H.J.; Chao H.T.;
Am. J. Hum. Genet. 106:570-583(2020)
Cited for: INVOLVEMENT IN LEUDEN; FUNCTION; VARIANTS LEUDEN LEU-11; SER-32; PHE-97; SER-109; VAL-109; PHE-133; SER-325 AND CYS-461; CHARACTERIZATION OF VARIANTS LEUDEN LEU-11; PHE-133 AND CYS-461; VARIANT GLN-114;
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.