UniProtKB/SwissProt variant VAR

Variant information

Variant position:

358

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

Type of variant:

LB/B

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:

From Aspartate (D) to Alanine (A) at position 358 (D358A, p.Asp358Ala).

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 medium size and acidic (D) to small size and hydrophobic (A)

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

Polymorphism:

Genetic variations in IL6R determine soluble IL6R serum levels [MIM:614689].Genetic variations in IL6R define the IL6 serum level quantitative trait locus [MIM:614752]. -

Additional information on the polymorphism described.

Variant description:

Significantly associated with circulating levels of IL6 and soluble IL6R; increases cleavage by ADAM17.

Any additional useful information about the variant.

Other resources:

Links to websites of interest for the variant.

Variant rs2228145 [ dbSNP | Ensembl ]

Sequence information

Variant position:

358

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

Protein sequence length:

468

The length of the canonical sequence.

Location on the sequence:

KDDDNILFRDSANATSLPVQ D SSSVPLPTFLVAGGSLAFGT

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                         KDDDNILFRDSANATSL--PVQDSSSVPLPTFLVAGGSLAFGT

Mouse                         SANHEDQYESSTEATSVLAPVQESSSMSLPTFLVAGGSLAF

Rat                           YDNHEDQYGSSTEATSVLAPVQGSSPIPLPTFLVAGGSLAF

Pig                           EDDEDISSKESANATSL--PVQDSASVPLPTFLVAGGSLAF

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.

Type	Positions	Description
Chain	20 – 468	Interleukin-6 receptor subunit alpha
Topological domain	20 – 365	Extracellular
Glycosylation	350 – 350	N-linked (GlcNAc...) asparagine
Glycosylation	352 – 352	O-linked (GlcNAc) threonine
Alternative sequence	356 – 365	VQDSSSVPLP -> GSRRRGSCGL. In isoform 2.
Mutagenesis	350 – 350	N -> A. No effect on IL6R signaling; when associated with A-55, A-93, A-221 and A-245. Loss of cleavage by ADAM17; when associated with A-55, A-93, A-221 and A-245.
Mutagenesis	352 – 352	T -> A. No effect on IL6R signaling.
Mutagenesis	355 – 355	P -> ID. Reduces cleavage by ADAM17.
Mutagenesis	356 – 356	V -> EG. Abolishes cleavage by ADAM17.

Literature citations

Complete sequencing and characterization of 21,243 full-length human cDNAs.
Ota T.; Suzuki Y.; Nishikawa T.; Otsuki T.; Sugiyama T.; Irie R.; Wakamatsu A.; Hayashi K.; Sato H.; Nagai K.; Kimura K.; Makita H.; Sekine M.; Obayashi M.; Nishi T.; Shibahara T.; Tanaka T.; Ishii S.; Yamamoto J.; Saito K.; Kawai Y.; Isono Y.; Nakamura Y.; Nagahari K.; Murakami K.; Yasuda T.; Iwayanagi T.; Wagatsuma M.; Shiratori A.; Sudo H.; Hosoiri T.; Kaku Y.; Kodaira H.; Kondo H.; Sugawara M.; Takahashi M.; Kanda K.; Yokoi T.; Furuya T.; Kikkawa E.; Omura Y.; Abe K.; Kamihara K.; Katsuta N.; Sato K.; Tanikawa M.; Yamazaki M.; Ninomiya K.; Ishibashi T.; Yamashita H.; Murakawa K.; Fujimori K.; Tanai H.; Kimata M.; Watanabe M.; Hiraoka S.; Chiba Y.; Ishida S.; Ono Y.; Takiguchi S.; Watanabe S.; Yosida M.; Hotuta T.; Kusano J.; Kanehori K.; Takahashi-Fujii A.; Hara H.; Tanase T.-O.; Nomura Y.; Togiya S.; Komai F.; Hara R.; Takeuchi K.; Arita M.; Imose N.; Musashino K.; Yuuki H.; Oshima A.; Sasaki N.; Aotsuka S.; Yoshikawa Y.; Matsunawa H.; Ichihara T.; Shiohata N.; Sano S.; Moriya S.; Momiyama H.; Satoh N.; Takami S.; Terashima Y.; Suzuki O.; Nakagawa S.; Senoh A.; Mizoguchi H.; Goto Y.; Shimizu F.; Wakebe H.; Hishigaki H.; Watanabe T.; Sugiyama A.; Takemoto M.; Kawakami B.; Yamazaki M.; Watanabe K.; Kumagai A.; Itakura S.; Fukuzumi Y.; Fujimori Y.; Komiyama M.; Tashiro H.; Tanigami A.; Fujiwara T.; Ono T.; Yamada K.; Fujii Y.; Ozaki K.; Hirao M.; Ohmori Y.; Kawabata A.; Hikiji T.; Kobatake N.; Inagaki H.; Ikema Y.; Okamoto S.; Okitani R.; Kawakami T.; Noguchi S.; Itoh T.; Shigeta K.; Senba T.; Matsumura K.; Nakajima Y.; Mizuno T.; Morinaga M.; Sasaki M.; Togashi T.; Oyama M.; Hata H.; Watanabe M.; Komatsu T.; Mizushima-Sugano J.; Satoh T.; Shirai Y.; Takahashi Y.; Nakagawa K.; Okumura K.; Nagase T.; Nomura N.; Kikuchi H.; Masuho Y.; Yamashita R.; Nakai K.; Yada T.; Nakamura Y.; Ohara O.; Isogai T.; Sugano S.;
Nat. Genet. 36:40-45(2004)
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2); VARIANT ALA-358;

Proteolytic Origin of the Soluble Human IL-6R In Vivo and a Decisive Role of N-Glycosylation.
Riethmueller S.; Somasundaram P.; Ehlers J.C.; Hung C.W.; Flynn C.M.; Lokau J.; Agthe M.; Duesterhoeft S.; Zhu Y.; Groetzinger J.; Lorenzen I.; Koudelka T.; Yamamoto K.; Pickhinke U.; Wichert R.; Becker-Pauly C.; Raedisch M.; Albrecht A.; Hessefort M.; Stahnke D.; Unverzagt C.; Rose-John S.; Tholey A.; Garbers C.;
PLoS Biol. 15:e2000080-e2000080(2017)
Cited for: FUNCTION; PROTEOLYTIC CLEAVAGE; TISSUE SPECIFICITY (ISOFORM 2); GLYCOSYLATION AT ASN-55; ASN-93; ASN-221; ASN-245; ASN-350 AND THR-352; MUTAGENESIS OF ASN-55; THR-57; ASN-93; ASN-221; ASN-245; ASN-350; THR-352; 355-PRO-VAL-356; PRO-355 AND VAL-356; CHARACTERIZATION OF VARIANT ALA-358; SUBCELLULAR LOCATION;

Admixture mapping of an allele affecting interleukin 6 soluble receptor and interleukin 6 levels.
Reich D.; Patterson N.; Ramesh V.; De Jager P.L.; McDonald G.J.; Tandon A.; Choy E.; Hu D.; Tamraz B.; Pawlikowska L.; Wassel-Fyr C.; Huntsman S.; Waliszewska A.; Rossin E.; Li R.; Garcia M.; Reiner A.; Ferrell R.; Cummings S.; Kwok P.Y.; Harris T.; Zmuda J.M.; Ziv E.;
Am. J. Hum. Genet. 80:716-726(2007)
Cited for: POLYMORPHISM; VARIANT ALA-358; ASSOCIATION OF VARIANT ALA-358 WITH IL6 AND SOLUBLE IL6R SERUM LEVELS;

UniProtKB/Swiss-Prot variant pages

UniProtKB/Swiss-Prot P08887: Variant p.Asp358Ala