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UniProtKB/Swiss-Prot Q15858: Variant p.Ala1643Thr

Sodium channel protein type 9 subunit alpha
Gene: SCN9A
Chromosomal location: 2q24.3
Variant information

Variant position:  1643
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 Alanine (A) to Threonine (T) at position 1643 (A1643T, p.Ala1643Thr).
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 hydrophobic (A) to medium size and polar (T)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  0
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:  Primary erythermalgia (PERYTHM) [MIM:133020]: Autosomal dominant disease characterized by recurrent episodes of severe pain associated with redness and warmth in the feet or hands. {ECO:0000269|PubMed:14985375, ECO:0000269|PubMed:15385606, ECO:0000269|PubMed:15955112, ECO:0000269|PubMed:15958509, ECO:0000269|PubMed:16216943, ECO:0000269|PubMed:16392115, ECO:0000269|PubMed:16702558, ECO:0000269|PubMed:16988069, ECO:0000269|PubMed:18945915, ECO:0000269|PubMed:19369487, ECO:0000269|PubMed:24311784}. 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 PERYTHM; no effect on voltage-dependence of channel activation; depolarizes the voltage dependence of steady-state fast inactivation; accelerates channel deactivation; no increase in persistent and resurgent currents; enhances neuronal hyperexcitability in dorsal root ganglion neurons.
Any additional useful information about the variant.



Sequence information

Variant position:  1643
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  1988
The length of the canonical sequence.

Location on the sequence:   LVKGAKGIRTLLFALMMSLP  A LFNIGLLLFLVMFIYAIFGM
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                         LVKGAKGIRTLLFALMMSLPALFNIGLLLFLVMFIYAIFGM

Mouse                         LIKGAKGIRTLLFALMMSLPALFNIGLLLFLVMFIYAIFGM

Rat                           LIKGAKGIRTLLFALMMSLPALFNIGLLLFLVMFIYAIFGM

Rabbit                        LIKGAKGIRTLLFALMMSLPALFNIGLLLFLVMFIYAIFGM

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 – 1988 Sodium channel protein type 9 subunit alpha
Topological domain 1625 – 1643 Cytoplasmic
Repeat 1497 – 1795 IV
Mutagenesis 1643 – 1643 A -> D. Depolarizes the voltage-dependence of steady-state fast inactivation; enhances persistent current.
Mutagenesis 1643 – 1643 A -> K. No effect on voltage-dependence of steady-state fast inactivation.
Mutagenesis 1643 – 1643 A -> V. No effect on voltage-dependence of steady-state fast inactivation.
Helix 1641 – 1666


Literature citations

Inherited pain: sodium channel Nav1.7 A1632T mutation causes erythromelalgia due to a shift of fast inactivation.
Eberhardt M.; Nakajima J.; Klinger A.B.; Neacsu C.; Huhne K.; O'Reilly A.O.; Kist A.M.; Lampe A.K.; Fischer K.; Gibson J.; Nau C.; Winterpacht A.; Lampert A.;
J. Biol. Chem. 289:1971-1980(2014)
Cited for: VARIANT PERYTHM THR-1643; CHARACTERIZATION OF VARIANT PERYTHM THR-1643; MUTAGENESIS OF ALA-1643; FUNCTION; SUBCELLULAR LOCATION;

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.