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UniProtKB/Swiss-Prot O75581: Variant p.Val1415Phe

Low-density lipoprotein receptor-related protein 6
Gene: LRP6
Variant information

Variant position:  1415
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  Unclassified
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 Valine (V) to Phenylalanine (F) at position 1415 (V1415F, p.Val1415Phe).
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 hydrophobic (V) to large size and aromatic (F)
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:  Found in a patient with congenital hydrocephalus; unknown pathological significance.
Any additional useful information about the variant.



Sequence information

Variant position:  1415
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  1613
The length of the canonical sequence.

Location on the sequence:   QRMLCPRMKGDGETMTNDYV  V HGPASVPLGYVPHPSSLSGS
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                         QRMLCPRMKGDGETMTNDYVVHGPASVPLGYVPHPSSLSGS

Mouse                         QRMLCPRMKGDGETMTNDYVVHSPASVPLGYVPHPSSLSGS

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 20 – 1613 Low-density lipoprotein receptor-related protein 6
Topological domain 1394 – 1613 Cytoplasmic
Modified residue 1420 – 1420 Phosphoserine; by CK1
Modified residue 1430 – 1430 Phosphoserine; by CK1
Lipidation 1399 – 1399 S-palmitoyl cysteine
Cross 1403 – 1403 Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)
Mutagenesis 1399 – 1399 C -> A. Some reduction of palmitoylation, and little change in plasma membrane location in the presence of MESD nor in Wnt-signaling activity. Completely abolishes palmitoylation, no plasma membrane location, greatly reduced Wnt-signaling activity but no effect on ubiquitination; when associated with A-1394. Exhibits full Wnt-signaling activity and no change in plasma membrane location in the in presence of MESD; when associated with A-1394 and R-1403.
Mutagenesis 1403 – 1403 K -> R. Abolishes ubiquitination, no change in plasma membrane location in the presence of MESD but greatly reduced Wnt-signaling activity. Exhibits full Wnt-signaling activity and no change in plasma membrane location; when associated with A-1394 and A-1399.
Mutagenesis 1420 – 1420 S -> A. Enhanced AXIN1 binding and increased beta-catenin activity by 2.2-fold. Further enhanced AXIN1 binding and increases beta-catenin activity by 3.3-fold; when associated with A-1430.
Mutagenesis 1430 – 1430 S -> A. Enhanced AXIN1 binding. Further enhanced AXIN1 binding and increases beta-catenin activity by 3.3-fold; when associated with A-1420.


Literature citations

De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus.
Furey C.G.; Choi J.; Jin S.C.; Zeng X.; Timberlake A.T.; Nelson-Williams C.; Mansuri M.S.; Lu Q.; Duran D.; Panchagnula S.; Allocco A.; Karimy J.K.; Khanna A.; Gaillard J.R.; DeSpenza T.; Antwi P.; Loring E.; Butler W.E.; Smith E.R.; Warf B.C.; Strahle J.M.; Limbrick D.D.; Storm P.B.; Heuer G.; Jackson E.M.; Iskandar B.J.; Johnston J.M.; Tikhonova I.; Castaldi C.; Lopez-Giraldez F.; Bjornson R.D.; Knight J.R.; Bilguvar K.; Mane S.; Alper S.L.; Haider S.; Guclu B.; Bayri Y.; Sahin Y.; Apuzzo M.L.J.; Duncan C.C.; DiLuna M.L.; Guenel M.; Lifton R.P.; Kahle K.T.;
Neuron 99:302-314.e4(2018)
Cited for: VARIANT PHE-1415;

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.