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UniProtKB/Swiss-Prot P08686: Variant p.Pro453Ser

Steroid 21-hydroxylase
Gene: CYP21A2
Variant information

Variant position:  453
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 Proline (P) to Serine (S) at position 453 (P453S, p.Pro453Ser).
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 hydrophobic (P) to small size and polar (S)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -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

Involvement in disease:  Adrenal hyperplasia 3 (AH3) [MIM:201910]: A form of congenital adrenal hyperplasia, a common recessive disease due to defective synthesis of cortisol. Congenital adrenal hyperplasia is characterized by androgen excess leading to ambiguous genitalia in affected females, rapid somatic growth during childhood in both sexes with premature closure of the epiphyses and short adult stature. Four clinical types: 'salt wasting' (SW, the most severe type), 'simple virilizing' (SV, less severely affected patients), with normal aldosterone biosynthesis, 'non-classic form' or late-onset (NC or LOAH) and 'cryptic' (asymptomatic). {ECO:0000269|PubMed:10051010, ECO:0000269|PubMed:10094562, ECO:0000269|PubMed:10198222, ECO:0000269|PubMed:10364682, ECO:0000269|PubMed:10391209, ECO:0000269|PubMed:10408778, ECO:0000269|PubMed:10408786, ECO:0000269|PubMed:10443693, ECO:0000269|PubMed:10496074, ECO:0000269|PubMed:10720040, ECO:0000269|PubMed:11232002, ECO:0000269|PubMed:11598371, ECO:0000269|PubMed:11600539, ECO:0000269|PubMed:11746135, ECO:0000269|PubMed:12213891, ECO:0000269|PubMed:12222711, ECO:0000269|PubMed:12788866, ECO:0000269|PubMed:12887291, ECO:0000269|PubMed:12915679, ECO:0000269|PubMed:1406699, ECO:0000269|PubMed:1406709, ECO:0000269|PubMed:14676460, ECO:0000269|PubMed:14715874, ECO:0000269|PubMed:1496017, ECO:0000269|PubMed:15110320, ECO:0000269|PubMed:15126570, ECO:0000269|PubMed:16046588, ECO:0000269|PubMed:1644925, ECO:0000269|PubMed:16984992, ECO:0000269|PubMed:18319307, ECO:0000269|PubMed:18381579, ECO:0000269|PubMed:18445671, ECO:0000269|PubMed:1864962, ECO:0000269|PubMed:1937474, ECO:0000269|PubMed:20080860, ECO:0000269|PubMed:2072928, ECO:0000269|PubMed:21169732, ECO:0000269|PubMed:22014889, ECO:0000269|PubMed:2303461, ECO:0000269|PubMed:27721825, ECO:0000269|PubMed:3038528, ECO:0000269|PubMed:3257825, ECO:0000269|PubMed:3260007, ECO:0000269|PubMed:3267225, ECO:0000269|PubMed:3497399, ECO:0000269|PubMed:3871526, ECO:0000269|PubMed:7749410, ECO:0000269|PubMed:8478006, ECO:0000269|PubMed:8485582, ECO:0000269|PubMed:8989258, ECO:0000269|PubMed:9067760, ECO:0000269|PubMed:9187661, ECO:0000269|PubMed:9497336, ECO:0000269|PubMed:9580109}. 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 AH3; non-classic form; simple virilizing form when associated with L-62; 50% of activity; almost completely abolished enzyme activity when associated with S-375.
Any additional useful information about the variant.

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



Sequence information

Variant position:  453
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  494
The length of the canonical sequence.

Location on the sequence:   LARLELFVVLTRLLQAFTLL  P SGDALPSLQPLPHCSVILKM
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                         LARLELFVVLTRLLQAFTLLPSG-DALPSLQPLPHCSVILKM

                              LARLELLVVLAQLLRAFTLMPAA-GTLPSLRPRARCGVNLS

Mouse                         LARLELFVVLARLLQAFTLLPPPDGTLPSLQPQPYAGINLP

Rat                           LARLEFFVVLARLLQTFTLLPPPDGTLPSLQPLPYTGINLL

Pig                           LARLELFVVLVQLLQAFTLLPPE-GALPSLQPHPHSGINLK

Bovine                        LARLELFVVLLRLLQAFTLLPPPVGALPSLQPDPYCGVNLK

Cat                           LARLELFVVLARLLHAFTLLPPT-GPLPSLRPRSHCGINLT

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 – 494 Steroid 21-hydroxylase
Beta strand 449 – 457


Literature citations

R339H and P453S: CYP21 mutations associated with nonclassic steroid 21-hydroxylase deficiency that are not apparent gene conversions.
Helmberg A.; Tusie-Luna M.-T.; Tabarelli M.; Kofler R.; White P.C.;
Mol. Endocrinol. 6:1318-1322(1992)
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]; VARIANTS LEU-9 INS; ARG-102 AND SER-493; VARIANTS AH3 HIS-339 AND SER-453;

Pro-453 to Ser mutation in CYP21 is associated with nonclassic steroid 21-hydroxylase deficiency.
Owerbach D.; Sherman L.; Ballard A.L.; Azziz R.;
Mol. Endocrinol. 6:1211-1215(1992)
Cited for: VARIANT AH3 SER-453;

Steroid 21-hydroxylase deficiency: three additional mutated alleles and establishment of phenotype-genotype relationships of common mutations.
Wedell A.; Ritzen E.M.; Haglund-Stengler B.; Luthman H.;
Proc. Natl. Acad. Sci. U.S.A. 89:7232-7236(1992)
Cited for: VARIANTS AH3 LEU-105; SER-291 AND SER-453;

Synergistic effect of partially inactivating mutations in steroid 21-hydroxylase deficiency.
Nikoshkov A.; Lajic S.; Holst M.; Wedell A.; Luthman H.;
J. Clin. Endocrinol. Metab. 82:194-199(1997)
Cited for: VARIANTS AH3 LEU-105 AND SER-453;

Mutation analysis in patients with congenital adrenal hyperplasia in the Spanish population: identification of putative novel steroid 21-hydroxylase deficiency alleles associated with the classic form of the disease.
Lobato M.N.; Ordonez-Sanchez M.L.; Tusie-Luna M.T.; Meseguer A.;
Hum. Hered. 49:169-175(1999)
Cited for: VARIANTS AH3 LEU-30; VAL-90; ASN-172; ALA-178; LEU-281; CYS-291; HIS-354; TRP-356 AND SER-453;

Characterization of single-nucleotide polymorphisms in coding regions of human genes.
Cargill M.; Altshuler D.; Ireland J.; Sklar P.; Ardlie K.; Patil N.; Shaw N.; Lane C.R.; Lim E.P.; Kalyanaraman N.; Nemesh J.; Ziaugra L.; Friedland L.; Rolfe A.; Warrington J.; Lipshutz R.; Daley G.Q.; Lander E.S.;
Nat. Genet. 22:231-238(1999)
Cited for: VARIANTS AH3 LEU-281 AND SER-453; VARIANTS THR-268 AND SER-493;

Predicting phenotype in steroid 21-hydroxylase deficiency? Comprehensive genotyping in 155 unrelated, well defined patients from southern Germany.
Krone N.; Braun A.; Roscher A.A.; Knorr D.; Schwarz H.P.;
J. Clin. Endocrinol. Metab. 85:1059-1065(2000)
Cited for: VARIANTS AH3 LEU-30; ASN-172; LEU-281; GLY-281; PHE-300; CYS-354; TRP-356 AND SER-453;

Phenotype-genotype correlation in 56 women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
Deneux C.; Tardy V.; Dib A.; Mornet E.; Billaud L.; Charron D.; Morel Y.; Kuttenn F.;
J. Clin. Endocrinol. Metab. 86:207-213(2001)
Cited for: VARIANTS AH3 LEU-30; ASN-172; LEU-281; MET-317; TRP-356; CYS-435 AND SER-453;

Mutational spectrum of the steroid 21-hydroxylase gene in Austria: identification of a novel missense mutation.
Baumgartner-Parzer S.M.; Schulze E.; Waldhaeusl W.; Pauschenwein S.; Rondot S.; Nowotny P.; Meyer K.; Frisch H.; Waldhauser F.; Vierhapper H.;
J. Clin. Endocrinol. Metab. 86:4771-4775(2001)
Cited for: VARIANTS AH3 LEU-30; ASN-172; LEU-281; SER-291; TRP-356; SER-424; HIS-426; SER-453 AND PRO-483; CHARACTERIZATION OF VARIANT AH3 HIS-426;

Non-classical 21-hydroxylase deficiency in children: association of adrenocorticotropic hormone-stimulated 17-hydroxyprogesterone with the risk of compound heterozygosity with severe mutations.
Ezquieta B.; Cueva E.; Varela J.; Oliver A.; Fernandez J.; Jariego C.;
Acta Paediatr. 91:892-898(2002)
Cited for: VARIANTS AH3 LEU-30; ASN-172; LEU-281; LEU-283; TRP-356 AND SER-453;

Novel mutations in CYP21 detected in individuals with hyperandrogenism.
Lajic S.; Clauin S.; Robins T.; Vexiau P.; Blanche H.; Bellanne-Chantelot C.; Wedell A.;
J. Clin. Endocrinol. Metab. 87:2824-2829(2002)
Cited for: VARIANTS HYPERANDROGENISM MET-304; SER-375 AND SER-453; CHARACTERIZATION OF VARIANTS HYPERANDROGENISM MET-304; SER-375 AND SER-453;

Mutational spectrum of congenital adrenal hyperplasia in Slovenian patients: a novel Ala15Thr mutation and Pro30Leu within a larger gene conversion associated with a severe form of the disease.
Dolzan V.; Stopar-Obreza M.; Zerjav-Tansek M.; Breskvar K.; Krzisnik C.; Battelino T.;
Eur. J. Endocrinol. 149:137-144(2003)
Cited for: VARIANTS AH3 THR-15; LEU-30; ASN-172; LEU-281 AND SER-453;

Follow-up of 68 children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency: relevance of genotype for management.
Pinto G.; Tardy V.; Trivin C.; Thalassinos C.; Lortat-Jacob S.; Nihoul-Fekete C.; Morel Y.; Brauner R.;
J. Clin. Endocrinol. Metab. 88:2624-2633(2003)
Cited for: VARIANTS AH3 LEU-30; LEU-62; ASN-172; LEU-281; PRO-341; TRP-356; SER-453 AND PRO-483;

Detection and assignment of CYP21 mutations using peptide mass signature genotyping.
Zeng X.; Witchel S.F.; Dobrowolski S.F.; Moulder P.V.; Jarvik J.W.; Telmer C.A.;
Mol. Genet. Metab. 82:38-47(2004)
Cited for: VARIANTS AH3 LEU-30; ASN-172; ASN-236; GLU-237; LYS-239; LEU-281; SER-291; GLN-356; TRP-356; TYR-365; SER-453; LEU-479 AND PRO-483; VARIANT ARG-102;

p.H62L, a rare mutation of the CYP21 gene identified in two forms of 21-hydroxylase deficiency.
Menassa R.; Tardy V.; Despert F.; Bouvattier-Morel C.; Brossier J.P.; Cartigny M.; Morel Y.;
J. Clin. Endocrinol. Metab. 93:1901-1908(2008)
Cited for: VARIANTS AH3 LEU-30; LEU-62; ASN-172; TRP-356 AND SER-453; CHARACTERIZATION OF VARIANTS AH3 LEU-62 AND SER-453;

Inhibition of CYP21A2 enzyme activity caused by novel missense mutations identified in Brazilian and Scandinavian patients.
Soardi F.C.; Barbaro M.; Lau I.F.; Lemos-Marini S.H.; Baptista M.T.; Guerra-Junior G.; Wedell A.; Lajic S.; de Mello M.P.;
J. Clin. Endocrinol. Metab. 93:2416-2420(2008)
Cited for: VARIANTS AH3 ARG-56; LEU-62; ARG-107; PRO-142; ASN-172; TRP-356; CYS-408 AND SER-453; CHARACTERIZATION OF VARIANTS AH3 ARG-56; LEU-62; ARG-107; PRO-142; CYS-408 AND SER-453;

Functional and structural consequences of a novel point mutation in the CYP21A2 gene causing congenital adrenal hyperplasia: potential relevance of helix C for P450 oxidoreductase-21-hydroxylase interaction.
Riepe F.G.; Hiort O.; Grotzinger J.; Sippell W.G.; Krone N.; Holterhus P.M.;
J. Clin. Endocrinol. Metab. 93:2891-2895(2008)
Cited for: VARIANTS AH3 GLN-121 AND SER-453; CHARACTERIZATION OF VARIANT AH3 GLN-121;

Phenotype-genotype correlations of 13 rare CYP21A2 mutations detected in 46 patients affected with 21-hydroxylase deficiency and in one carrier.
Tardy V.; Menassa R.; Sulmont V.; Lienhardt-Roussie A.; Lecointre C.; Brauner R.; David M.; Morel Y.;
J. Clin. Endocrinol. Metab. 95:1288-1300(2010)
Cited for: VARIANTS AH3 THR-77; PRO-167; ASN-172; THR-230; LYS-233; LEU-281; SER-291; ASP-292; LYS-320; PRO-341; HIS-354; TRP-356; TRP-369; CYS-408; SER-424; HIS-426 AND SER-453; CHARACTERIZATION OF VARIANTS AH3 PRO-167; ASN-172; LEU-281; ASP-292; LYS-320; TRP-369 AND SER-424;

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.