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UniProtKB/Swiss-Prot variant pages

UniProtKB/Swiss-Prot Q9UHW9: Variant p.Thr991Ala

Solute carrier family 12 member 6
Gene: SLC12A6
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Variant information Variant position: help 991 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Type of variant: help LP/P [Disclaimer] The variants are classified into three categories: LP/P, LB/B and US.
  • LP/P: likely pathogenic or pathogenic.
  • LB/B: likely benign or benign.
  • US: uncertain significance
Residue change: help From Threonine (T) to Alanine (A) at position 991 (T991A, p.Thr991Ala). 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: help Change from medium size and polar (T) to small size and hydrophobic (A) The physico-chemical property of the reference and variant residues and the change implicated.
BLOSUM score: help 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
Variant description: help In CMT2II; abolished WNK kinase-dependent inhibitory phosphorylation; constitutively enhanced potassium-chloride cotransport activity; reduced acute swelling response to hypotonic stress. Any additional useful information about the variant.


Sequence information Variant position: help 991 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length: help 1150 The length of the canonical sequence.
Location on the sequence: help AEVEVVEMHDSDISAYTYER T LMMEQRSQMLRHMRLSKTER 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: help The multiple alignment of the region surrounding the variant against various orthologous sequences. 
Human                         AEVEVVEMHDSDISAYTYERTLMMEQRSQMLRHMRLSKTER

Mouse                         AEVEVVEMHDSDISAYTYERTLMMEQRSQMLRHMRLSKTER
Sequence annotation in neighborhood: help 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 – 1150 Solute carrier family 12 member 6
Topological domain 666 – 1150 Cytoplasmic
Modified residue 981 – 981 Phosphoserine
Modified residue 991 – 991 Phosphothreonine; by OXSR1 and STK39
Mutagenesis 991 – 991 T -> A. Decreased phosphorylation by WNK kinases, leading to increased potassium-chloride cotransport activity. Increases Rb(+) uptake; when associated with D-96 and D-1048.
Mutagenesis 991 – 991 T -> D. Decreases Rb(+) uptake; when associated with D-96 and D-1048.
Turn 991 – 993



Literature citations
Peripheral motor neuropathy is associated with defective kinase regulation of the KCC3 cotransporter.
Kahle K.T.; Flores B.; Bharucha-Goebel D.; Zhang J.; Donkervoort S.; Hegde M.; Hussain G.; Duran D.; Liang B.; Sun D.; Boennemann C.G.; Delpire E.;
Sci. Signal. 9:ra77-ra77(2016)
Cited for: INVOLVEMENT IN CMT2II; VARIANT CMT2II ALA-991; CHARACTERIZATION OF VARIANT CMT2II ALA-991; FUNCTION; PHOSPHORYLATION AT THR-991;
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.