Home  |  Contact

UniProtKB/Swiss-Prot O43541: Variant p.Arg465Cys

Mothers against decapentaplegic homolog 6
Gene: SMAD6
Variant information

Variant position:  465
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 Arginine (R) to Cysteine (C) at position 465 (R465C, p.Arg465Cys).
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 large size and basic (R) to medium size and polar (C)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -3
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:  Craniosynostosis 7 (CRS7) [MIM:617439]: A form of craniosynostosis, a primary abnormality of skull growth involving premature fusion of one or more cranial sutures. The growth velocity of the skull often cannot match that of the developing brain resulting in an abnormal head shape and, in some cases, increased intracranial pressure, which must be treated promptly to avoid permanent neurodevelopmental disability. {ECO:0000269|PubMed:27606499}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Rare heterozygous SMAD6 variants are strongly associated with non-syndromic midline craniosynostosis and confer a very high risk for disease development, in the presence of a common risk allele (rs1884302) near the BMP2 locus. {ECO:0000269|PubMed:27606499}.
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 CRS7; associated with disease susceptibility.
Any additional useful information about the variant.

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

Sequence information

Variant position:  465
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  496
The length of the canonical sequence.

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.




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.

Chain 1 – 496 Mothers against decapentaplegic homolog 6
Domain 331 – 496 MH2
Alternative sequence 339 – 496 Missing. In isoform D.
Mutagenesis 471 – 471 G -> S. Loss of SMAD1-binding and of inhibition of BMP-SMAD1 signaling. No effect on interaction with BMPR1B and TGFBR1.

Literature citations

Two locus inheritance of non-syndromic midline craniosynostosis via rare SMAD6 and common BMP2 alleles.
Timberlake A.T.; Choi J.; Zaidi S.; Lu Q.; Nelson-Williams C.; Brooks E.D.; Bilguvar K.; Tikhonova I.; Mane S.; Yang J.F.; Sawh-Martinez R.; Persing S.; Zellner E.G.; Loring E.; Chuang C.; Galm A.; Hashim P.W.; Steinbacher D.M.; DiLuna M.L.; Duncan C.C.; Pelphrey K.A.; Zhao H.; Persing J.A.; Lifton R.P.;
Elife 5:0-0(2016)
Cited for: INVOLVEMENT IN CRS7; VARIANTS CRS7 223-GLN--ARG-496 DEL; LYS-287; ALA-306; LEU-323; 374-GLU--ARG-496 DEL; CYS-390; 407-GLU--ARG-496 DEL; CYS-465 AND THR-490;

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.