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UniProtKB/Swiss-Prot variant pages

UniProtKB/Swiss-Prot O43291: Variant p.Tyr163Cys

Kunitz-type protease inhibitor 2
Gene: SPINT2
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Variant information Variant position: help 163 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 Tyrosine (Y) to Cysteine (C) at position 163 (Y163C, p.Tyr163Cys). 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 large size and aromatic (Y) to medium size and polar (C) The physico-chemical property of the reference and variant residues and the change implicated.
BLOSUM score: help -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
Variant description: help In DIAR3; pathogenic; has a significantly reduced ability to inhibit trypsin compared to wild-type; reduced peptidase inhibitor activity toward prostasin; decreased inhibition of prostasin is due to abnormal SPINT2 glycosylation. Any additional useful information about the variant.
Other resources: help Links to websites of interest for the variant.


Sequence information Variant position: help 163 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length: help 252 The length of the canonical sequence.
Location on the sequence: help RASFPRWYFDVERNSCNNFI Y GGCRGNKNSYRSEEACMLRC 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                         RASFPRWYFDVERNSCNNFIYGGCRGNKNSYRSEEACMLRC

Mouse                         RAAFPRWYYDTEKNSCISFIYGGCRGNKNSYLSQEACMQHC
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 28 – 252 Kunitz-type protease inhibitor 2
Topological domain 28 – 197 Extracellular
Domain 133 – 183 BPTI/Kunitz inhibitor 2
Disulfide bond 133 – 183
Disulfide bond 142 – 166
Disulfide bond 158 – 179



Literature citations
Mutations in SPINT2 cause a syndromic form of congenital sodium diarrhea.
Heinz-Erian P.; Mueller T.; Krabichler B.; Schranz M.; Becker C.; Rueschendorf F.; Nuernberg P.; Rossier B.; Vujic M.; Booth I.W.; Holmberg C.; Wijmenga C.; Grigelioniene G.; Kneepkens C.M.F.; Rosipal S.; Mistrik M.; Kappler M.; Michaud L.; Doczy L.-C.; Siu V.M.; Krantz M.; Zoller H.; Utermann G.; Janecke A.R.;
Am. J. Hum. Genet. 84:188-196(2009)
Cited for: VARIANT DIAR3 CYS-163; CHARACTERIZATION OF VARIANT DIAR3 CYS-163; INVOLVEMENT IN DIAR3; Case of syndromic tufting enteropathy harbors SPINT2 mutation seen in congenital sodium diarrhea.
Sivagnanam M.; Janecke A.R.; Mueller T.; Heinz-Erian P.; Taylor S.; Bird L.M.;
Clin. Dysmorphol. 19:48-48(2010)
Cited for: VARIANT DIAR3 CYS-163; INVOLVEMENT IN DIAR3; Genetic characterization of congenital tufting enteropathy: epcam associated phenotype and involvement of SPINT2 in the syndromic form.
Salomon J.; Goulet O.; Canioni D.; Brousse N.; Lemale J.; Tounian P.; Coulomb A.; Marinier E.; Hugot J.P.; Ruemmele F.; Dufier J.L.; Roche O.; Bodemer C.; Colomb V.; Talbotec C.; Lacaille F.; Campeotto F.; Cerf-Bensussan N.; Janecke A.R.; Mueller T.; Koletzko S.; Bonnefont J.P.; Lyonnet S.; Munnich A.; Poirier F.; Smahi A.;
Hum. Genet. 133:299-310(2014)
Cited for: VARIANTS DIAR3 83-GLU--LEU-252 DEL; CYS-148; CYS-163 AND SER-168; INVOLVEMENT IN DIAR3; Congenital sodium diarrhea and chorioretinal coloboma with optic disc coloboma in a patient with biallelic SPINT2 mutations, including p.(Tyr163Cys).
Hirabayashi K.E.; Moore A.T.; Mendelsohn B.A.; Taft R.J.; Chawla A.; Perry D.; Henry D.; Slavotinek A.;
Am. J. Med. Genet. A 176:997-1000(2018)
Cited for: VARIANT DIAR3 CYS-163; SPINT2 (HAI-2) missense variants identified in congenital sodium diarrhea/tufting enteropathy affect the ability of HAI-2 to inhibit prostasin but not matriptase.
Holt-Danborg L.; Vodopiutz J.; Nonboe A.W.; De Laffolie J.; Skovbjerg S.; Wolters V.M.; Mueller T.; Hetzer B.; Querfurt A.; Zimmer K.P.; Jensen J.K.; Entenmann A.; Heinz-Erian P.; Vogel L.K.; Janecke A.R.;
Hum. Mol. Genet. 28:828-841(2019)
Cited for: VARIANTS DIAR3 149-TRP--LEU-252 DEL; VAL-161 AND CYS-163; CHARACTERIZATION OF VARIANTS DIAR3 VAL-161; CYS-163 AND SER-168; FUNCTION; SPINT2 mutations in the Kunitz domain 2 found in SCSD patients inactivate HAI-2 as prostasin inhibitor via abnormal protein folding and N-glycosylation.
Huang N.; Wang Q.; Bernard R.B.; Chen C.Y.; Hu J.M.; Wang J.K.; Chan K.S.; Johnson M.D.; Lin C.Y.;
Hum. Mol. Genet. 0:0-0(2024)
Cited for: CHARACTERIZATION OF VARIANTS DIAR3 HIS-148; CYS-148 AND CYS-163;
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.