UniProtKB/Swiss-Prot P04049: Variant p.Ser257Leu

RAF proto-oncogene serine/threonine-protein kinase
Gene: RAF1
Chromosomal location: 3p25
Variant information

Variant position:  257
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 Serine (S) to Leucine (L) at position 257 (S257L, p.Ser257Leu).
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 polar (S) to medium size and hydrophobic (L)
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:  LEOPARD syndrome 2 (LPRD2) [MIM:611554]: A disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness. {ECO:0000269|PubMed:17603483}. 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.

Involvement in disease:  Noonan syndrome 5 (NS5) [MIM:611553]: A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells. {ECO:0000269|PubMed:17603482, ECO:0000269|PubMed:17603483, ECO:0000269|PubMed:20683980}. 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 NS5 and LPRD2; shows in vitro greater kinase activity and enhanced ERK activation than wild-type.
Any additional useful information about the variant.

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



Sequence information

Variant position:  257
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:   AFTFNTSSPSSEGSLSQRQR  S TSTPNVHMVSTTLPVDSRMI
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                         AFTFNT---SSPSSEGSLSQ--RQRSTSTPNVHMVSTTLPVDSRMI

Mouse                         AFTFNT---SSPSSEGSLSQ--RQRSTSTPNVHMVSTTLHV

Rat                           AFTFNT---SSPSSEGSLSQ--RQRSTSTPNVHMVSTTLPV

Bovine                        AFTFSA---SSPSSEGSLSQ--RQRSTSTPNVHMVSATLPV

Chicken                       VFTFNT---SNPSSEGTLSQ--RQRSTSTPNVHMVSTTMPV

Xenopus laevis                PFSFST---PSPVSECSLSQ--RQRSTSTPNVHMVSTTMAV

Fission yeast                 IGDFHSETIQSLESHYKLNQVGEKEYSTISDLCFSKGNLFL

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
Modified residue 252 – 252 Phosphoserine
Modified residue 259 – 259 Phosphoserine; by PKA, PKC and PKB/AKT1
Modified residue 268 – 268 Phosphothreonine; by autocatalysis
Modified residue 269 – 269 Phosphothreonine; by PKA


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;

Germline gain-of-function mutations in RAF1 cause Noonan syndrome.
Razzaque M.A.; Nishizawa T.; Komoike Y.; Yagi H.; Furutani M.; Amo R.; Kamisago M.; Momma K.; Katayama H.; Nakagawa M.; Fujiwara Y.; Matsushima M.; Mizuno K.; Tokuyama M.; Hirota H.; Muneuchi J.; Higashinakagawa T.; Matsuoka R.;
Nat. Genet. 39:1013-1017(2007)
Cited for: VARIANTS NS5 LEU-257; ALA-261; SER-261; ALA-263 AND VAL-613; CHARACTERIZATION OF VARIANTS NS5 LEU-257; ALA-261; SER-261; ALA-263 AND 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.