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UniProtKB/Swiss-Prot variant pages

UniProtKB/Swiss-Prot Q96QP1: Variant p.Thr237Met

Alpha-protein kinase 1
Gene: ALPK1
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Variant information Variant position: help 237 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 Methionine (M) at position 237 (T237M, p.Thr237Met). 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 medium size and hydrophobic (M) The physico-chemical property of the reference and variant residues and the change implicated.
BLOSUM score: help -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: help In ROSAH; pathogenic; gain-of-function variant resulting in increased NF-kappaB signaling; the mutant protein is constitutively active in absence of ADP-Heptose; contrary to the wild type, it is activated by UDP-alpha-D-mannose and ADP-D-ribose. Any additional useful information about the variant.
Other resources: help Links to websites of interest for the variant.


Sequence information Variant position: help 237 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length: help 1244 The length of the canonical sequence.
Location on the sequence: help IWASIVGYLALPQPDKKGLS T SLGILADIFVSMSKNDYEKF 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                         IWASIVGYLALPQPDKKGLSTSLGILADIFVSMSKNDYEKF

Mouse                         IWASVIGYLTLPQPDKKGISTSLGILADIFVSMSKTDYEKF
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 – 1244 Alpha-protein kinase 1
Binding site 231 – 231
Binding site 233 – 233
Binding site 236 – 237
Mutagenesis 231 – 231 D -> A. Impaired ADP-D-glycero-beta-D-manno-heptose-binding and ability to activate the serine/threonine-protein kinase activity; when associated with A-67.
Mutagenesis 233 – 233 K -> A. Impaired ADP-D-glycero-beta-D-manno-heptose-binding and ability to activate the serine/threonine-protein kinase activity.
Mutagenesis 237 – 237 T -> E. Impaired ADP-D-glycero-beta-D-manno-heptose-binding and ability to activate the serine/threonine-protein kinase activity; when associated with K-295.
Helix 232 – 248



Literature citations
ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder.
Williams L.B.; Javed A.; Sabri A.; Morgan D.J.; Huff C.D.; Grigg J.R.; Heng X.T.; Khng A.J.; Hollink I.H.I.M.; Morrison M.A.; Owen L.A.; Anderson K.; Kinard K.; Greenlees R.; Novacic D.; Nida Sen H.; Zein W.M.; Rodgers G.M.; Vitale A.T.; Haider N.B.; Hillmer A.M.; Ng P.C.; Shankar A.; Cheng A.; Zheng L.; Gillies M.C.; van Slegtenhorst M.; van Hagen P.M.; Missotten T.O.A.R.; Farley G.L.; Polo M.; Malatack J.; Curtin J.; Martin F.; Arbuckle S.; Alexander S.I.; Chircop M.; Davila S.; Digre K.B.; Jamieson R.V.; DeAngelis M.M.;
Genet. Med. 21:2103-2115(2019)
Cited for: VARIANT ROSAH MET-237; INVOLVEMENT IN ROSAH; TISSUE SPECIFICITY; FUNCTION; SUBCELLULAR LOCATION;
Juvenile Onset Splenomegaly and Oculopathy Due to Germline Mutation in ALPK1.
Zhong L.; Wang J.; Wang W.; Wang L.; Quan M.; Tang X.; Gou L.; Wei M.; Xiao J.; Zhang T.; Sui R.; Zhou Q.; Song H.;
J. Clin. Immunol. 40:350-358(2020)
Cited for: VARIANT ROSAH MET-237; INVOLVEMENT IN ROSAH;
Gain-of-function mutations in ALPK1 cause an NF-kappaB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome.
Kozycki C.T.; Kodati S.; Huryn L.; Wang H.; Warner B.M.; Jani P.; Hammoud D.; Abu-Asab M.S.; Jittayasothorn Y.; Mattapallil M.J.; Tsai W.L.; Ullah E.; Zhou P.; Tian X.; Soldatos A.; Moutsopoulos N.; Kao-Hsieh M.; Heller T.; Cowen E.W.; Lee C.R.; Toro C.; Kalsi S.; Khavandgar Z.; Baer A.; Beach M.; Long Priel D.; Nehrebecky M.; Rosenzweig S.; Romeo T.; Deuitch N.; Brenchley L.; Pelayo E.; Zein W.; Sen N.; Yang A.H.; Farley G.; Sweetser D.A.; Briere L.; Yang J.; de Oliveira Poswar F.; Schwartz I.V.D.; Silva Alves T.; Dusser P.; Kone-Paut I.; Touitou I.; Titah S.M.; van Hagen P.M.; van Wijck R.T.A.; van der Spek P.J.; Yano H.; Benneche A.; Apalset E.M.; Jansson R.W.; Caspi R.R.; Kuhns D.B.; Gadina M.; Takada H.; Ida H.; Nishikomori R.; Verrecchia E.; Sangiorgi E.; Manna R.; Brooks B.P.; Sobrin L.; Hufnagel R.B.; Beck D.; Shao F.; Ombrello A.K.; Aksentijevich I.; Kastner D.L.;
Ann. Rheum. Dis. 81:1453-1464(2022)
Cited for: VARIANTS ROSAH MET-237 AND CYS-254; CHARACTERIZATION OF VARIANTS ROSAH MET-237 AND CYS-254; INVOLVEMENT IN ROSAH; FUNCTION;
ALPK1 mutants causing ROSAH syndrome or Spiradenoma are activated by human nucleotide sugars.
Snelling T.; Saalfrank A.; Wood N.T.; Cohen P.;
Proc. Natl. Acad. Sci. U.S.A. 120:e2313148120-e2313148120(2023)
Cited for: CHARACTERIZATION OF VARIANTS ROSAH MET-237 AND CYS-254; MUTAGENESIS OF VAL-1092; FUNCTION;
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.