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UniProtKB/Swiss-Prot P04049: Variant p.Thr491Ile

RAF proto-oncogene serine/threonine-protein kinase
Gene: RAF1
Variant information

Variant position:  491
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  LP/P [Disclaimer]
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 Threonine (T) to Isoleucine (I) at position 491 (T491I, p.Thr491Ile).
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 polar (T) to medium size and hydrophobic (I)
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

Variant description:  In NS5; has reduced or absent kinase activity.
Any additional useful information about the variant.

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



Sequence information

Variant position:  491
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  648
The length of the canonical sequence.

Location on the sequence:   SNNIFLHEGLTVKIGDFGLA  T VKSRWSGSQQVEQPTGSVLW
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                         SNNIFLHEGLTVKIGDFGLATVKS------RWSGSQQVEQPTGSVLW

Mouse                         SNNIFLHEGLTVKIGDFGLATVKS------RWSGSQQVEQP

Rat                           SNNIFLHEGLTVKIGDFGLATVKS------RWSGSQQVEQP

Bovine                        SNNIFLHEGLTVKIGDFGLATVKS------RWSGSQQVEQP

Chicken                       SNNIFLHEGLTVKIGDFGLATVKS------RWSGSQQVEQP

Xenopus laevis                SNNIFLHEGLTVKIGDFGLATVKT------RWSGSQQVEQL

Fission yeast                 DNQTFVWDS---RKPDKPLSLLKHGKTKMIHFDGANEEEVD

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 1 – 648 RAF proto-oncogene serine/threonine-protein kinase
Domain 349 – 609 Protein kinase
Modified residue 471 – 471 Phosphoserine
Modified residue 491 – 491 Phosphothreonine
Modified residue 494 – 494 Phosphoserine
Modified residue 499 – 499 Phosphoserine; by PKC
Mutagenesis 491 – 491 T -> D. Increased kinase activity but can still be inhibited by PPP5C; when associated with D-494.
Mutagenesis 494 – 494 S -> D. Increased kinase activity but can still be inhibited by PPP5C; when associated with D-491.


Literature citations

Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy.
Pandit B.; Sarkozy A.; Pennacchio L.A.; Carta C.; Oishi K.; Martinelli S.; Pogna E.A.; Schackwitz W.; Ustaszewska A.; Landstrom A.; Bos J.M.; Ommen S.R.; Esposito G.; Lepri F.; Faul C.; Mundel P.; Lopez Siguero J.P.; Tenconi R.; Selicorni A.; Rossi C.; Mazzanti L.; Torrente I.; Marino B.; Digilio M.C.; Zampino G.; Ackerman M.J.; Dallapiccola B.; Tartaglia M.; Gelb B.D.;
Nat. Genet. 39:1007-1012(2007)
Cited for: VARIANTS NS5 SER-256; PHE-259; ARG-260; LEU-261; SER-261; ASN-486; GLY-486; ILE-491; ARG-491 AND THR-612; VARIANT HYPERTROPHIC CARDIOMYOPATHY ILE-260; VARIANTS LPRD2 LEU-257 AND VAL-613; VARIANT NS5 LEU-257; CHARACTERIZATION OF VARIANTS NS5 SER-261; ASN-486 AND ILE-491; CHARACTERIZATION OF VARIANT LPRD2 VAL-613;

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.