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UniProtKB/Swiss-Prot O43541: Variant p.Cys484Phe

Mothers against decapentaplegic homolog 6
Gene: SMAD6
Variant information

Variant position:  484
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 Cysteine (C) to Phenylalanine (F) at position 484 (C484F, p.Cys484Phe).
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 (C) to large size and aromatic (F)
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:  Aortic valve disease 2 (AOVD2) [MIM:614823]: A common defect in the aortic valve in which two rather than three leaflets are present. It is often associated with aortic valve calcification, stenosis and insufficiency. In extreme cases, the blood flow may be so restricted that the left ventricle fails to grow, resulting in hypoplastic left heart syndrome. {ECO:0000269|PubMed:22275001}. Note=The disease is caused by mutations affecting the gene represented in this entry. SMAD6 variants may contribute to increased risk of congenital cardiovascular malformations (CVM). CVM is a major cause of mortality and morbidity in childhood. In most sporadic cases that cannot be attributed to particular malformation syndromes or teratogenic exposures, there remains a substantial excess familial risk, indicating a significant genetic contribution to disease susceptibility (PubMed:22275001). {ECO:0000269|PubMed:22275001}.
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 AOVD2; results in significantly lower activity than wild-type in inhibiting BMP signaling in a transcriptional reporter assay.
Any additional useful information about the variant.

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



Sequence information

Variant position:  484
The position of the amino-acid change on the UniProtKB canonical protein sequence.

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

Location on the sequence:   VRISFAKGWGPCYSRQFITS  C PCWLEILLNNPR
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                         VRISFAKGWGPCYSRQFITSCPCWLEILLNNPR

Mouse                         VRISFAKGWGPCYSRQFITSCPCWLEILLNNHR

Chicken                       VRISFAKGWGPCYSRQFITSCPCWLEILLSNNR

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 – 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.
Mutagenesis 478 – 496 Missing. Loss of interaction with BMPR1B, TGFBR1 and SMAD1.


Literature citations

Nonsynonymous variants in the SMAD6 gene predispose to congenital cardiovascular malformation.
Tan H.L.; Glen E.; Topf A.; Hall D.; O'Sullivan J.J.; Sneddon L.; Wren C.; Avery P.; Lewis R.J.; ten Dijke P.; Arthur H.M.; Goodship J.A.; Keavney B.D.;
Hum. Mutat. 33:720-727(2012)
Cited for: INVOLVEMENT IN CONGENITAL CARDIOVASCULAR MALFORMATIONS; VARIANT THR-325; VARIANTS AOVD2 LEU-415 AND PHE-484; CHARACTERIZATION OF VARIANTS AOVD2 LEU-415 AND PHE-484;

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.