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UniProtKB/Swiss-Prot Q02094: Variant p.Phe65Ser

Ammonium transporter Rh type A
Gene: RHAG
Chromosomal location: 6p11-p21.1
Variant information

Variant position:  65
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 Phenylalanine (F) to Serine (S) at position 65 (F65S, p.Phe65Ser).
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 large size and aromatic (F) to small size and polar (S)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -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

Involvement in disease:  Overhydrated hereditary stomatocytosis (OHST) [MIM:185000]: An autosomal dominant disorder of red cell membrane permeability to monovalent cations, characterized by macrocytic hemolytic anemia of fluctuating severity, circulating erythrocytes with slit-like lucencies (stomata) evident on fixed, stained peripheral blood smears. OHST red cells exhibit cation leak, resulting in elevated cell sodium content with reduced potassium content. The disease is marked by splenomegaly or hepatosplenomegaly, cholelithiasis and a strong tendency for iron overload. {ECO:0000269|PubMed:18931342, ECO:0000269|PubMed:21849667, ECO:0000269|PubMed:22012326}. 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 OHST; enhances monovalent cation leak; decreases ammonium fluxes; highly decreases STOM expression; decreases membrane expression; no effect on water permeability.
Any additional useful information about the variant.

Other resources:  
Links to websites of interest for the variant.



Sequence information

Variant position:  65
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  409
The length of the canonical sequence.

Location on the sequence:   GIFFELYPLFQDVHVMIFVG  F GFLMTFLKKYGFSSVGINLL
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                         G--IFFELYPLFQDVHVMIFVGFGFLMTFLKKYGFSSVGINLL

                              D--RSLELYPLFQDVHVMIFVGFGFLMTFLKKYGFSSVGIN

Mouse                         D--QFFQLYPLFQDVHVMIFVGFGFLMTFLKKYGFSGVGFN

Rat                           D--QFFQLYPLFQHVHVMIFVGFGFLMTFLKKYGFSGVGFN

Bovine                        DVEKTMESYPFFQDVHIMVFAGFGFLMTFLWKYGFSGVGIN

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 – 409 Ammonium transporter Rh type A
Transmembrane 52 – 72 Helical


Literature citations

The monovalent cation leak in overhydrated stomatocytic red blood cells results from amino acid substitutions in the Rh-associated glycoprotein.
Bruce L.J.; Guizouarn H.; Burton N.M.; Gabillat N.; Poole J.; Flatt J.F.; Brady R.L.; Borgese F.; Delaunay J.; Stewart G.W.;
Blood 113:1350-1357(2009)
Cited for: INVOLVEMENT IN OHST; VARIANTS OHST ARG-61 AND SER-65; CHARACTERIZATION OF VARIANTS OHST ARG-61 AND SER-65; FUNCTION; TISSUE SPECIFICITY; SUBCELLULAR LOCATION; GLYCOSYLATION;

Loss-of-function and gain-of-function phenotypes of stomatocytosis mutant RhAG F65S.
Stewart A.K.; Shmukler B.E.; Vandorpe D.H.; Rivera A.; Heneghan J.F.; Li X.; Hsu A.; Karpatkin M.; O'Neill A.F.; Bauer D.E.; Heeney M.M.; John K.; Kuypers F.A.; Gallagher P.G.; Lux S.E.; Brugnara C.; Westhoff C.M.; Alper S.L.;
Am. J. Physiol. 301:C1325-C1343(2011)
Cited for: VARIANT OHST SER-65; CHARACTERIZATION OF VARIANT OHST SER-65; FUNCTION;

Human RhAG ammonia channel is impaired by the Phe65Ser mutation in overhydrated stomatocytic red cells.
Genetet S.; Ripoche P.; Picot J.; Bigot S.; Delaunay J.; Armari-Alla C.; Colin Y.; Mouro-Chanteloup I.;
Am. J. Physiol. 302:C419-C428(2012)
Cited for: CHARACTERIZATION OF VARIANT OHST SER-65; FUNCTION; SUBCELLULAR LOCATION; GLYCOSYLATION; TISSUE SPECIFICITY;

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.