CYP21A2

cytochrome P450 family 21 subfamily A member 2, the group of Cytochrome P450 family 21

Basic information

Region (hg38): 6:32038327-32041644

Previous symbols: [ "CYP21", "CYP21B" ]

Links

ENSG00000231852 ∙ NCBI:1589 ∙ OMIM:613815 ∙ HGNC:2600 ∙ Uniprot:P08686 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (Definitive), mode of inheritance: AR
• classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (Strong), mode of inheritance: AR
• classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form (Supportive), mode of inheritance: AR
• classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form (Supportive), mode of inheritance: AR
• classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Adrenal hyperplasia, congenital, due to 21-hydroxylase deficiency	AR	Cardiovascular; Endocrine; Genitourinary; Oncologic	In classic 21-OHD CAH, medical therapy (with glucocorticoid replacement), including with stress dosing glucocorticoid replacement therapy is beneficial; In the salt-wasting form, medical therapy (eg, with mineralocorticoid therapy, sodium chloride) can be beneficial; Surveillance and early treatment for neoplasms such as testicular adrenal rest tumors is indicated, as is surveillance related to multiple factors such as BMI, bone mineral density, fertility, and cardiovascular risk factors	Cardiovascular; Endocrine; Genitourinary; Oncologic	13968788; 4298539; 835605; 152409; 6449518; 6102330; 317470; 6095106; 2989686; 3030300; 3491959; 3038528; 2667968; 2783976; 2247119; 1311000; 1644925; 7957400; 8855797; 8626833; 8923864; 9360525; 9329356; 9100612; 8989258; 9851787; 9661649; 9613359; 9829208; 10372672; 10084573; 10199755; 10720040; 11070100; 0720048; 11397874; 11232002; 11397897; 11739428; 12107196; 12213842; 12183722; 12788866; 12930931; 12915679; 12843131; 14764770; 16926248; 17299071; 17878254; 17535996; 17148562; 17456574; 8989258; 18381579; 20392211; 20301350; 22841790; 23073904; 22157069; 22241917; 22802425; 23044877; 22186144

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CYP21A2 gene.

• not provided (32 variants)
• Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (12 variants)
• CYP21A2-related disorder (5 variants)
• Congenital adrenal hyperplasia (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CYP21A2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous	3		2	9	8	22
missense	18	26	43	3	3	93
nonsense	9	3				12
start loss	1					1
frameshift	6	6	1			13
inframe indel			1		1	2
splice donor/acceptor (+/-2bp)	1	3				4
splice region			4	2	1	7
non coding		1	7	11	11	30
Total	38	39	54	23	23

Highest pathogenic variant AF is 0.00378

Variants in CYP21A2

This is a list of pathogenic ClinVar variants found in the CYP21A2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
6-32038342-A-C		CYP21A2-related disorder	Uncertain significance (Jan 22, 2024)
6-32038350-C-T		CYP21A2-related disorder	Uncertain significance (Oct 21, 2022)
6-32038415-G-A			Likely benign (Jul 26, 2022)
6-32038419-C-T		not specified	Benign (Oct 08, 2021)
6-32038423-A-G			Pathogenic (Oct 29, 2021)
6-32038437-CCTG-C		not specified	Benign (Jul 18, 2017)
6-32038437-C-CCTG		21-HYDROXYLASE POLYMORPHISM • Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	Benign (Jun 01, 1987)
6-32038441-C-CT		Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	Likely pathogenic (-)
6-32038444-C-A		not specified	Uncertain significance (Feb 14, 2023)
6-32038459-C-A		Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	Uncertain significance (Jan 20, 2023)
6-32038462-G-T		Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	Uncertain significance (May 11, 2022)
6-32038467-C-T			Uncertain significance (Mar 14, 2016)
6-32038471-C-T		not specified • Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	Uncertain significance (Apr 25, 2023)
6-32038472-G-T		Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	Uncertain significance (May 24, 2019)
6-32038481-G-A		Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	Pathogenic (Jul 17, 2023)
6-32038482-G-A			Pathogenic (Oct 10, 2022)
6-32038490-G-A		Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	Likely pathogenic (Mar 17, 2024)
6-32038491-G-T		not specified	Uncertain significance (Apr 19, 2016)
6-32038499-G-A		CYP21A2-related disorder	Uncertain significance (Nov 27, 2023)
6-32038505-T-TC		Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	Pathogenic (Dec 01, 2001)
6-32038511-T-A			Uncertain significance (Jun 20, 2018)
6-32038513-C-T		Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	Likely pathogenic (Apr 14, 2023)
6-32038514-C-A			Pathogenic (Nov 23, 2018)
6-32038514-C-T		Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	Pathogenic (Jul 16, 2023)
6-32038516-C-T			Uncertain significance (Aug 23, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CYP21A2	protein_coding	protein_coding	ENST00000418967	10	3406

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000260	0.985	125722	0	26	125748	0.000103

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.15	219	273	0.803	0.0000168	3086
Missense in Polyphen		83	102.75	0.80778		1178
Synonymous	1.37	99	118	0.839	0.00000754	1003
Loss of Function	2.16	9	19.2	0.469	8.44e-7	232

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000580	0.0000580
Ashkenazi Jewish	0.00	0.00
East Asian	0.000961	0.000816
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.0000562	0.0000527
Middle Eastern	0.000961	0.000816
South Asian	0.00	0.00
Other	0.000190	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Specifically catalyzes the 21-hydroxylation of steroids. Required for the adrenal synthesis of mineralocorticoids and glucocorticoids (PubMed:22014889). {ECO:0000269|PubMed:22014889, ECO:0000269|PubMed:25855791, ECO:0000269|PubMed:27721825}.
• Disease: 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.
• Pathway: Cortisol synthesis and secretion - Homo sapiens (human);Aldosterone synthesis and secretion - Homo sapiens (human);Cushing,s syndrome - Homo sapiens (human);Steroid hormone biosynthesis - Homo sapiens (human);Steroidogenesis;Apparent mineralocorticoid excess syndrome;3-Beta-Hydroxysteroid Dehydrogenase Deficiency;21-hydroxylase deficiency (CYP21);Corticosterone methyl oxidase I deficiency (CMO I);Corticosterone methyl oxidase II deficiency - CMO II;Adrenal Hyperplasia Type 5 or Congenital Adrenal Hyperplasia due to 17 Alpha-hydroxylase Deficiency;Adrenal Hyperplasia Type 3 or Congenital Adrenal Hyperplasia due to 21-hydroxylase Deficiency;Congenital Lipoid Adrenal Hyperplasia (CLAH) or Lipoid CAH;17-alpha-hydroxylase deficiency (CYP17);11-beta-hydroxylase deficiency (CYP11B1);Corticotropin-releasing hormone signaling pathway;Glucocorticoid and Mineralcorticoid Metabolism;Metapathway biotransformation Phase I and II;Phase I - Functionalization of compounds;Metabolism of lipids;Endogenous sterols;Cytochrome P450 - arranged by substrate type;Biological oxidations;Metabolism;Mineralocorticoid biosynthesis;Metabolism of steroid hormones;Metabolism of steroids;C21-steroid hormone biosynthesis and metabolism;Glucocorticoid biosynthesis;glucocorticoid biosynthesis;mineralocorticoid biosynthesis;superpathway of steroid hormone biosynthesis;Steroid hormones (Consensus)

Recessive Scores

• pRec: 0.264

Haploinsufficiency Scores

• pHI: 0.273
• hipred: Y
• hipred_score: 0.507
• ghis: 0.408

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.810

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Cps1
• Phenotype: homeostasis/metabolism phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span)

Zebrafish Information Network

• Gene name: cyp21a2
• Affected structure: interrenal gland
• Phenotype tag: abnormal
• Phenotype quality: hyperplastic

Gene ontology

• Biological process: steroid biosynthetic process;glucocorticoid biosynthetic process;mineralocorticoid biosynthetic process;steroid metabolic process;sterol metabolic process;oxidation-reduction process
• Cellular component: endoplasmic reticulum membrane;organelle membrane
• Molecular function: steroid 21-monooxygenase activity;steroid binding;iron ion binding;steroid hydroxylase activity;heme binding