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UniProtKB/Swiss-Prot P42898: Variant p.Ala222Val

Methylenetetrahydrofolate reductase
Gene: MTHFR
Variant information

Variant position:  222
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 Alanine (A) to Valine (V) at position 222 (A222V, p.Ala222Val).
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 small size and hydrophobic (A) to medium size and hydrophobic (V)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  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

Polymorphism:  Genetic variation in MTHFR influences susceptibility to occlusive vascular disease, neural tube defects (NTD), colon cancer and acute leukemia.
Additional information on the polymorphism described.

Variant description:  At homozygosity reduces the risk for colorectal cancer in individuals with adequate folate status; decreased risk for adult acute leukemia; increased risk for NTDFS; increased risk for schizophrenia; thermolabile; decreased affinity for FAD cofactor; 50% reduced activity.
Any additional useful information about the variant.

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



Sequence information

Variant position:  222
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  656
The length of the canonical sequence.

Location on the sequence:   PEAGSFEADLKHLKEKVSAG  A DFIITQLFFEADTFFRFVKA
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.

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 – 656 Methylenetetrahydrofolate reductase
Binding site 210 – 210 FAD
Binding site 217 – 217 FAD
Binding site 228 – 228 Substrate


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] (ISOFORM 1); VARIANT VAL-222;

Submission
NIEHS SNPs program;
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]; VARIANTS GLN-68; VAL-222; ARG-422; ALA-429; CYS-519; GLN-594 AND MET-653;

A meta-analysis of the MTHFR C677T polymorphism and schizophrenia risk.
Lewis S.J.; Zammit S.; Gunnell D.; Smith G.D.;
Am. J. Med. Genet. B Neuropsychiatr. Genet. 135B:2-4(2005)
Cited for: INVOLVEMENT IN SCZD; VARIANT VAL-222;

Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database.
Allen N.C.; Bagade S.; McQueen M.B.; Ioannidis J.P.; Kavvoura F.K.; Khoury M.J.; Tanzi R.E.; Bertram L.;
Nat. Genet. 40:827-834(2008)
Cited for: INVOLVEMENT IN SCZD; VARIANT VAL-222;

Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida.
van der Put N.M.J.; Steegers-Theunissen R.P.M.; Frosst P.; Trijbels F.J.M.; Eskes T.K.A.B.; van den Heuvel L.P.; Mariman E.C.M.; den Heyer M.; Rozen R.; Blom H.J.;
Lancet 346:1070-1071(1995)
Cited for: INVOLVEMENT IN SUSCEPTIBILITY TO NTDFS; VARIANT VAL-222;

A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase.
Frosst P.; Blom H.J.; Milos R.; Goyette P.; Sheppard C.A.; Matthews R.G.; Boers G.J.H.; den Heijer M.; Kluijtmans L.A.J.; van den Heuvel L.P.; Rozen R.;
Nat. Genet. 10:111-113(1995)
Cited for: VARIANT VAL-222;

5,10 Methylenetetrahydrofolate reductase genetic polymorphism as a risk factor for neural tube defects.
Ou C.Y.; Stevenson R.E.; Brown V.K.; Schwartz C.E.; Allen W.P.; Khoury M.J.; Rozen R.; Oakley G.P. Jr.; Adams M.J. Jr.;
Am. J. Med. Genet. 63:610-614(1996)
Cited for: INVOLVEMENT IN SUSCEPTIBILITY TO NTDFS; VARIANT VAL-222;

A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer.
Chen J.; Giovannucci E.; Kelsey K.; Rimm E.B.; Stampfer M.J.; Colditz G.A.; Spiegelman D.; Willett W.C.; Hunter D.J.;
Cancer Res. 56:4862-4864(1996)
Cited for: INVERSE ASSOCIATION OF VARIANT VAL-222 WITH COLORECTAL CANCER;

Worldwide distribution of a common methylenetetrahydrofolate reductase mutation.
Schneider J.A.; Rees D.C.; Liu Y.-T.; Clegg J.B.;
Am. J. Hum. Genet. 62:1258-1260(1998)
Cited for: VARIANT VAL-222;

Genetic polymorphisms in methylenetetrahydrofolate reductase and methionine synthase, folate levels in red blood cells, and risk of neural tube defects.
Christensen B.; Arbour L.; Tran P.; Leclerc D.; Sabbaghian N.; Platt R.; Gilfix B.M.; Rosenblatt D.S.; Gravel R.A.; Forbes P.; Rozen R.;
Am. J. Med. Genet. 84:151-157(1999)
Cited for: INVOLVEMENT IN SUSCEPTIBILITY TO NTDFS; VARIANT VAL-222;

Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults.
Skibola C.F.; Smith M.T.; Kane E.; Roman E.; Rollinson S.; Cartwright R.A.; Morgan G.;
Proc. Natl. Acad. Sci. U.S.A. 96:12810-12815(1999)
Cited for: VARIANTS VAL-222 AND ALA-429; ASSOCIATION WITH SUSCEPTIBILITY TO ACUTE LEUKEMIA;

Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18,000 cases and 58,000 controls.
Casas J.P.; Hingorani A.D.; Bautista L.E.; Sharma P.;
Arch. Neurol. 61:1652-1661(2004)
Cited for: ASSOCIATION OF VARIANT VAL-222 WITH SUSCEPTIBILITY TO ISCHSTR;

Molecular characterization of five patients with homocystinuria due to severe methylenetetrahydrofolate reductase deficiency.
Urreizti R.; Moya-Garcia A.A.; Pino-Angeles A.; Cozar M.; Langkilde A.; Fanhoe U.; Esteves C.; Arribas J.; Vilaseca M.A.; Perez-Duenas B.; Pineda M.; Gonzalez V.; Artuch R.; Baldellou A.; Vilarinho L.; Fowler B.; Ribes A.; Sanchez-Jimenez F.; Grinberg D.; Balcells S.;
Clin. Genet. 78:441-448(2010)
Cited for: VARIANTS MTHFRD LEU-218; SER-435 AND GLY-574; CHARACTERIZATION OF VARIANT MTHFRD LEU-218; CHARACTERIZATION OF VARIANT VAL-222; COFACTOR;

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.