CYP21A2

Summary

CYP21A2 (cytochrome P450 family 21 subfamily A member 2, HGNC:2600) is a protein-coding gene on chromosome 6p21.33, encoding Steroid 21-hydroxylase (P08686). A cytochrome P450 monooxygenase that plays a major role in adrenal steroidogenesis.

This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and hydroxylates steroids at the 21 position. Its activity is required for the synthesis of steroid hormones including cortisol and aldosterone. Mutations in this gene cause congenital adrenal hyperplasia. A related pseudogene is located near this gene; gene conversion events involving the functional gene and the pseudogene are thought to account for many cases of steroid 21-hydroxylase deficiency. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 1589 — RefSeq curated summary.

At a glance

• Gene–disease (curated): classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (Definitive, GenCC) — +2 more curated relationships
• GWAS associations: 37
• Clinical variants (ClinVar): 405 total — 69 pathogenic, 47 likely-pathogenic
• Phenotypes (HPO): 13
• Druggable target: yes — 4 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_000500

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2600
Approved symbol	CYP21A2
Name	cytochrome P450 family 21 subfamily A member 2
Location	6p21.33
Locus type	gene with protein product
Status	Approved
Aliases	P450c21B, CA21H, CPS1, CAH1
Ensembl gene	ENSG00000231852
Ensembl biotype	protein_coding
OMIM	613815
Entrez	1589

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 17 protein_coding, 9 retained_intron, 2 nonsense_mediated_decay

ENST00000435122, ENST00000462278, ENST00000464325, ENST00000466779, ENST00000466879, ENST00000469053, ENST00000471671, ENST00000478281, ENST00000479074, ENST00000479730, ENST00000480027, ENST00000483041, ENST00000486063, ENST00000488465, ENST00000644719, ENST00000960595, ENST00000960596, ENST00000960597, ENST00000960598, ENST00000960599, ENST00000960600, ENST00000960601, ENST00000960602, ENST00000960603, ENST00000960604, ENST00000960605, ENST00000960606, ENST00000960607

RefSeq mRNA: 4 — MANE Select: NM_000500 NM_000500, NM_001128590, NM_001368143, NM_001368144

CCDS: CCDS4735, CCDS47406

Canonical transcript exons

ENST00000436607 — 0 exons

Expression profiles

Bgee: expression breadth ubiquitous, 130 present calls, max score 99.87.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1190 / max 203.7094, expressed in 5 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
67111	0.0774	5
67110	0.0417	2

Top tissues by expression

133 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland	UBERON:0001233	99.87	gold quality
left adrenal gland	UBERON:0001234	99.85	gold quality
right adrenal gland cortex	UBERON:0035827	99.84	gold quality
left adrenal gland cortex	UBERON:0035825	99.79	gold quality
adrenal tissue	UBERON:0018303	99.62	gold quality
adrenal gland	UBERON:0002369	98.89	gold quality
right lobe of liver	UBERON:0001114	92.13	gold quality
liver	UBERON:0002107	85.70	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.15	gold quality
left ovary	UBERON:0002119	75.10	gold quality
spleen	UBERON:0002106	75.05	gold quality
right ovary	UBERON:0002118	74.55	gold quality
ovary	UBERON:0000992	73.59	gold quality
mucosa of stomach	UBERON:0001199	73.55	gold quality
metanephros cortex	UBERON:0010533	73.49	gold quality
sural nerve	UBERON:0015488	72.84	gold quality
adult mammalian kidney	UBERON:0000082	72.56	gold quality
muscle layer of sigmoid colon	UBERON:0035805	72.27	gold quality
lower esophagus	UBERON:0013473	72.23	gold quality
left uterine tube	UBERON:0001303	72.19	gold quality
lower esophagus muscularis layer	UBERON:0035833	72.18	gold quality
adenohypophysis	UBERON:0002196	71.11	gold quality
minor salivary gland	UBERON:0001830	71.08	gold quality
saliva-secreting gland	UBERON:0001044	70.46	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	70.12	gold quality
tibial nerve	UBERON:0001323	69.32	gold quality
pituitary gland	UBERON:0000007	68.86	gold quality
cortical plate	UBERON:0005343	68.74	gold quality
right coronary artery	UBERON:0001625	68.72	gold quality
omental fat pad	UBERON:0010414	68.37	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-9543	yes	21.60
E-ANND-3	no	0.29

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): DGKQ, NR2C2, NR4A1, NR4A2, NR5A1, TCF3

miRNA regulators (miRDB)

49 targeting CYP21A2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-133A-5P	99.28	69.13	941
HSA-MIR-3160-3P	99.07	64.78	955
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-320A-5P	98.88	66.75	1248
HSA-MIR-3135B	98.61	65.33	1470
HSA-MIR-6754-5P	98.60	65.54	1627
HSA-MIR-6887-5P	98.56	68.49	1295
HSA-MIR-6795-5P	98.52	68.51	1277
HSA-MIR-3928-5P	98.50	67.48	980
HSA-MIR-6806-3P	98.50	67.31	980
HSA-MIR-6842-3P	98.07	66.33	1325
HSA-MIR-7113-5P	97.88	67.33	1735
HSA-MIR-127-5P	97.78	67.64	869
HSA-MIR-3652	97.71	65.43	1890
HSA-MIR-558	97.50	67.16	977

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Functional analysis after expression in COS-1 cells revealed that the mutant enzymes had reduced enzymatic activity for conversion of both 17-hydroxyprogesterone (L300F 9.5%, V281G 3.9% of normal) and progesterone (L300F 4.4%, V281G 3.9% of normal). (PMID:11692155)
• DNA mutational analysis in Scottish patients; correlation of genotype with phenotype in any identified carriers (PMID:12038604)
• Genetic analysis of Japanese patients with 21-hydroxylase deficiency: new mutation of a homozygous deletion of adenine at codon 246. (PMID:12050231)
• Novel mutations in CYP21 detected in individuals with hyperandrogenism. (PMID:12050257)
• molecular studies on RCCX haplotypes revealing a unique recombination giving rise to a TNXB/TNXA hybrid gene, CYP21A deletion and CYP21B duplication on one chromosome (PMID:12121677)
• in at least some patients, CYP21 mutations may play a role in the pathomechanism of bilateral and unilateral adrenal incidentalomas (PMID:12213672)
• Three novel mutations in Brazilian patients with the classical form of 21-hydroxylase deficiency due to a founder effect (PMID:12213891)
• role of duplication in complicating mutation analysis in congenital adrenal hyperplasia (PMID:12384784)
• CYP21 binding sites for progesterone enantiomers are analyzed (PMID:12464252)
• chromosomal mapping of a de novo unequal crossover causing a deletion of the steroid 21-hydroxylase gene and a non-functional hybrid tenascin-X gene (PMID:12746407)
• Coexistence of two mutations caused by deletion of CYP21P, XA, RP2, and C4B genes and intergenic recombination in C4-CYP21 repeat module. Haplotype of mutated CYP21 gene has not been reported as gene deletion. (PMID:12788880)
• Maternal haplotype, inherited by brother, has duplicated CYP21B gene. One carries Q318X mutation. (PMID:12788889)
• duplication of 111 bases from codons 21 to 57 inserted at codon 58 in exon 1 of the CYP21 gene was found in congenital adrenal hyperplasia; the 5’ end region showed the sequence of the CYP21P gene at nucleotides (nt) -103, -110, -123, and thereafter (PMID:12855227)
• six novel mutations and a specific cluster of four mutations in 21-hydroxylase deficient patients in The Netherlands (PMID:12915679)
• Three putative novel mutations in congenital adrenal hyperplasia. (PMID:14676460)
• Young adults with 21-hydroxylase deficiency had a short stature and broad bones with a normal bone mineral content and had an increased fat mass percentage. (PMID:14676461)
• Analysis of the distribution of CYP21 gene mutations in Chinese population samples from 52 patients with 21-hydroxylase deficiency may provide important information for genetic counseling and for prenatal diagnosis. (PMID:14733808)
• In late-onset congenital adrenal hyperplasia, the most common mutation (Val281-Leu, V281L) was found in 10 patients (7 heterozygous/3 homozygous). The frequency of V281L mutation was found as 32.5% in 20 patients. (PMID:15004406)
• Carrier frequency of 9.5 per cent of aberrations in this gene involving congenital adrenal hyperplasia. (PMID:15572419)
• CYP21-carrier status could not explain the observed high prevalence of abnormal ACTH-stimulated 17OHP levels in the hirsute population. (PMID:15598692)
• CYP21 mutations seem to play a limited role in the development of polycystic ovary syndrome in the population studied (PMID:15705377)
• Two brothers are described. One was diagnosed with simple virilizing CAH and was able to maintain sodium balance during salt deprivation tests. Patient 2, was diagnosed with salt-wasting CAH and was unable to maintain sodium balance. (PMID:15751603)
• The most frequent mutations in the CYP21 gene were del-CYP21 (25%), I172N (22%) and i2g (15%); unlike in other ethnic groups, there was no R356W mutation, but a higher rate of del-8bp (10%) was found in our population (PMID:15775714)
• Four patients of the androgen excess group were identified as heterozygous carriers of CYP21 mutations. (PMID:15793784)
• combination of in vitro enzyme function and computerized protein analysis of the E351 residue of the CYP21 protein provides experimental evidence for the ERR triad being a fundamental structural element of cytochrome P450 enzymes (PMID:15830218)
• Genotyping as a new approach of genetic counseling, prediction of clinical form after screening for deficiency (review) (PMID:15988383)
• P482S CYP21 gene mutation was associated with loss of heterozygosity (PMID:16500637)
• Four mutations of CYP21A2 associated with severe enzyme deficiency and are predicted to cause classic CAH if found in trans with other mutations causing severe enzyme deficiency (PMID:16541276)
• Molecular model of human CYP21. (PMID:16788163)
• Four new CYP21A2 missense mutations (C169R, G178R, W302R, and R426C)in Congenital Adrenal Hyperplasia. (PMID:16984992)
• Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency in two infertile male patients, leading to infertility. (PMID:17033937)
• The characterization of four additional missense mutations in CYP21, is reported. (PMID:17119906)
• review of genetic structure of 21-hydoxylase and mutations that give rise to 21-hydroxylase deficiency (PMID:17466088)
• Elevated body mass index was not a determining factor in the development of hypertension in children with 21-hydroxylase deficiency. (PMID:17526939)
• frequency of CYP21 V281L mutation in congenital adrenal hyperplasia patients of the different ethnic groups varied and was a reflection of the frequency found in the healthy population (high in Ashkenzai, lower in non-Ashkenazi), very low in Israeli arabs (PMID:17551464)
• Three novel mutations were found in the CYP21A2 gene and predicted to drastically impair enzyme activity resulting in severe classic congenital adrenal hyperplasia. (PMID:17573904)
• Microconversions between CYP21A2 and CYP21A1P promoters could be involved in the nonclassical phenotype of 21-hydroxylase deficiency (PMID:17666484)
• Women with 21-hydroxylase deficiency have low bone mineral density and increased fracture risk (PMID:17878254)
• V281+I172N/V281L genotype should be included in the panel of mutations associated with the non-classical forms of 21-hydroxylase deficiency. (PMID:18028896)
• CYP21A2 deletion in the ethnic Chinese (Taiwanese) patients exhibits a low occurrence, with the haplotype of the IVS2-12A/C>G in combination with the 707-714del mutation (without the P30L mutation) being prevalent among large gene deletions or conversions (PMID:18039588)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cyp21a2	ENSDARG00000037550
mus_musculus	Cyp21a1	ENSMUSG00000024365
rattus_norvegicus	Cyp21a1	ENSRNOG00000000428

Protein

Protein identifiers

Steroid 21-hydroxylase — P08686 (reviewed: P08686)

Alternative names: 21-OHase, Cytochrome P-450c21, Cytochrome P450 21, Cytochrome P450 XXI, Cytochrome P450-C21, Cytochrome P450-C21B

All UniProt accessions (6): E7EN87, E7ERT7, E7EVC0, P08686, F8WBR4, K9LII7

UniProt curated annotations — full annotation on UniProt →

Function. A cytochrome P450 monooxygenase that plays a major role in adrenal steroidogenesis. Catalyzes the hydroxylation at C-21 of progesterone and 17alpha-hydroxyprogesterone to respectively form 11-deoxycorticosterone and 11-deoxycortisol, intermediate metabolites in the biosynthetic pathway of mineralocorticoids and glucocorticoids. Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase).

Subcellular location. Endoplasmic reticulum membrane. Microsome membrane.

Disease relevance. 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). The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The leucine-rich hydrophobic amino acid N-terminal region probably helps to anchor the protein to the microsomal membrane.

Polymorphism. Several non deleterious alleles have been described including CYP21A21A, CYP21A21B, CYP21A22, CYP21A23, CYP21A24, CYP21A25 and CYP21A2*6. Deleterious alleles are mostly generated by recombinations between CYP21A2 and the pseudogene CYP21A1P through gene conversion. This process consists of recombination events that either delete CYP21A2 or transfer deleterious mutations from CYP21A1P to CYP21A2.

Similarity. Belongs to the cytochrome P450 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P08686-1	1	yes
P08686-2	2

RefSeq proteins (4): NP_000491, NP_001122062, NP_001355072, NP_001355073 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001128	Cyt_P450	Family
IPR002401	Cyt_P450_E_grp-I	Family
IPR017972	Cyt_P450_CS	Conserved_site
IPR036396	Cyt_P450_sf	Homologous_superfamily

Pfam: PF00067

Enzyme classification (BRENDA):

• EC 1.14.14.16 — steroid 21-monooxygenase (BRENDA: 7 organisms, 54 substrates, 42 inhibitors, 69 Km, 36 kcat entries)

Substrate kinetics (BRENDA)

5 substrates with measured Km, best-characterized 5. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
PROGESTERONE	0.0002–9.2	31
17ALPHA-HYDROXYPROGESTERONE	0.0004–0.022	29
17-HYDROXY-PROGESTERONE	2.3–9.2	3
17-HYDROXYPROGESTERONE	0.0038–0.031	3
17A-HYDROXYPROGESTERONE	—	0

Catalyzed reactions (Rhea), 2 shown:

• progesterone + reduced [NADPH–hemoprotein reductase] + O2 = 21-hydroxyprogesterone + oxidized [NADPH–hemoprotein reductase] + H2O + H(+) (RHEA:50304)
• 17alpha-hydroxyprogesterone + reduced [NADPH–hemoprotein reductase] + O2 = 11-deoxycortisol + oxidized [NADPH–hemoprotein reductase] + H2O + H(+) (RHEA:50308)

UniProt features (142 total): sequence variant 82, helix 22, strand 12, sequence conflict 8, binding site 7, turn 5, mutagenesis site 4, chain 1, splice variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
4Y8W	X-RAY DIFFRACTION	2.64
5VBU	X-RAY DIFFRACTION	3.31

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P08686-F1	92.87	0.84

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (7): 92; 121; 234; 234; 366; 427; 429 (axial binding residue)

Mutagenesis-validated functional residues (4):

Position	Phenotype
269	no effect on progesterone 21-hydroxylase activity.
282	decreased 21-hydroxylase activity. normal km but 50% reduced vmax.
282	decreased 21-hydroxylase activity. normal km but 10% reduced vmax.
429	loss of progesterone 21-hydroxylase activity and loss of p450 absorption.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-193993	Mineralocorticoid biosynthesis
R-HSA-194002	Glucocorticoid biosynthesis
R-HSA-211976	Endogenous sterols
R-HSA-5579021	Defective CYP21A2 causes AH3

MSigDB gene sets: 422 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_EPITHELIUM_DEVELOPMENT, REACTOME_BIOLOGICAL_OXIDATIONS, GOBP_RESPONSE_TO_ZINC_ION, YAGI_AML_WITH_INV_16_TRANSLOCATION, CCAWYNNGAAR_UNKNOWN, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_RESPONSE_TO_AMINE, GOBP_RESPONSE_TO_ACID_CHEMICAL, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_RESPONSE_TO_CORTICOSTEROID, GOBP_GLUCOCORTICOID_METABOLIC_PROCESS

GO Biological Process (8): steroid biosynthetic process (GO:0006694), glucocorticoid biosynthetic process (GO:0006704), mineralocorticoid biosynthetic process (GO:0006705), steroid metabolic process (GO:0008202), sterol metabolic process (GO:0016125), cortisol biosynthetic process (GO:0034651), lipid metabolic process (GO:0006629), hormone metabolic process (GO:0042445)

GO Molecular Function (13): steroid 21-monooxygenase activity (GO:0004509), steroid binding (GO:0005496), iron ion binding (GO:0005506), steroid hydroxylase activity (GO:0008395), heme binding (GO:0020037), 17-hydroxyprogesterone 21-hydroxylase activity (GO:0103069), progesterone 21-hydroxylase activity (GO:0106309), monooxygenase activity (GO:0004497), lipid binding (GO:0008289), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen (GO:0016705), oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen (GO:0016712), metal ion binding (GO:0046872)

GO Cellular Component (3): endoplasmic reticulum membrane (GO:0005789), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Metabolism of steroid hormones	2
Cytochrome P450 - arranged by substrate type	1
Metabolic disorders of biological oxidation enzymes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
steroid metabolic process	2
steroid hormone biosynthetic process	2
monooxygenase activity	2
steroid 21-monooxygenase activity	2
oxidoreductase activity	2
lipid biosynthetic process	1
glucocorticoid metabolic process	1
mineralocorticoid metabolic process	1
hormone biosynthetic process	1
lipid metabolic process	1
glucocorticoid biosynthetic process	1
primary alcohol biosynthetic process	1
cortisol metabolic process	1
ketone biosynthetic process	1
olefinic compound biosynthetic process	1
tertiary alcohol biosynthetic process	1
primary metabolic process	1
metabolic process	1
regulation of hormone levels	1
steroid hydroxylase activity	1
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen	1
lipid binding	1
transition metal ion binding	1
tetrapyrrole binding	1
binding	1
catalytic activity	1
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen	1
cation binding	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

4 interactions, top by confidence:

A	B	Type	Score
CYP21A2	HSPD1	psi-mi:“MI:0915”(physical association)	0.400
CYP21A2	EEF1D	psi-mi:“MI:0915”(physical association)	0.400
FECH	POTEF	psi-mi:“MI:0914”(association)	0.350

BioGRID (24): CYP21A2 (Two-hybrid), CYP21A2 (Two-hybrid), CYP21A2 (Two-hybrid), CYP21A2 (Two-hybrid), CYP21A2 (Two-hybrid), CYP21A2 (Two-hybrid), CYP21A2 (Two-hybrid), CYP21A2 (Two-hybrid), CYP21A2 (Two-hybrid), CYP21A2 (Two-hybrid), CYP21A2 (Two-hybrid), KRTAP9-2 (Two-hybrid), LCE1F (Two-hybrid), LCE3C (Two-hybrid), KRTAP4-2 (Two-hybrid)

ESM2 similar proteins: A0A087X1C5, E9Q816, O18992, O46658, P00191, P03940, P08686, P10633, P10634, P10635, P11714, P12394, P12938, P12939, P15540, P24456, P24457, P30437, P51589, P51590, P52786, P70085, P78329, Q01361, Q0IIF9, Q29473, Q29488, Q2LA59, Q2LA60, Q2LCM1, Q2XNC8, Q2XNC9, Q4V8D1, Q64403, Q64562, Q64680, Q6GUQ4, Q6VVW9, Q6VVX0, Q7Z449

Diamond homologs: A0A067F4I6, A0A067GFT7, A0A068Q721, A0A098DJ84, A0A161GJD5, A0A1B2CTB6, A0A1L9WVI3, A0A1V1FNM9, A0A1V1FNZ5, A0A2K9RG08, A0A2P1DPA5, A0A397HSG2, A0A3Q9R4N5, A0A517FND1, A0A7G9U7M0, A0A9E7S4M4, A1C8C2, A8C7R4, B1NF19, B5UAQ8, C9K1X6, D1MX85, D7UQ39, F1SY70, F1SY75, G1XU01, I3PFJ5, L0E2R0, L8AXV5, M1WEN7, O04790, O15528, O23976, O35084, O48928, O48956, O49340, O49342, O64635, O64636

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
CYP21A2	“up-regulates quantity”	17alpha-hydroxyprogesterone	“chemical modification”
CYP21A2	“down-regulates quantity”	11-deoxycortisol	“chemical modification”
CYP21A2	“up-regulates quantity”	11-deoxycorticosterone	“chemical modification”
CYP21A2	“down-regulates quantity”	progesterone	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

405 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	69
Likely pathogenic	47
Uncertain significance	141
Likely benign	37
Benign	52

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1119979	NM_000500.9(CYP21A2):c.651+2T>G	Pathogenic
1119995	NM_000500.9(CYP21A2):c.833dup (p.Glu279fs)	Pathogenic
1174727	NM_000500.9(CYP21A2):c.949C>T (p.Arg317Ter)	Pathogenic
12150	NM_000500.9(CYP21A2):c.518T>A (p.Ile173Asn)	Pathogenic
12152	NM_000500.9(CYP21A2):c.1069C>T (p.Arg357Trp)	Pathogenic
12159	NM_000500.9(CYP21A2):c.1360C>T (p.Pro454Ser)	Pathogenic
12160	CYP21A2, 30-KB DEL	Pathogenic
12161	CYP21A2, GENE CONVERSION CYP21 FROM CYP21P	Pathogenic
12164	NM_000500.9(CYP21A2):c.332_339del (p.Gly111fs)	Pathogenic
12168	NM_000500.9(CYP21A2):c.939+1G>C	Pathogenic
12169	NM_000500.7(CYP21A2):c.955C>T (p.Gln319Ter)	Pathogenic
12171	NM_000500.9(CYP21A2):c.1217G>A (p.Trp406Ter)	Pathogenic
12175	NM_000500.9(CYP21A2):c.1280G>A (p.Arg427His)	Pathogenic
12176	NM_000500.9(CYP21A2):c.85dup (p.His29fs)	Pathogenic
12177	NM_000500.9(CYP21A2):c.293-2A>G	Pathogenic
12178	NM_000500.9(CYP21A2):c.511dup (p.Ser171fs)	Pathogenic
12179	NM_000500.9(CYP21A2):c.1225C>T (p.Arg409Cys)	Pathogenic
12181	NM_000500.9(CYP21A2):c.1126G>A (p.Gly376Ser)	Pathogenic
1341485	NM_000500.9(CYP21A2):c.1019G>A (p.Arg340His)	Pathogenic
1422248	NM_000500.9(CYP21A2):c.1024C>T (p.Arg342Trp)	Pathogenic
1451630	NM_000500.9(CYP21A2):c.1A>G (p.Met1Val)	Pathogenic
1451631	NM_000500.9(CYP21A2):c.116A>T (p.His39Leu)	Pathogenic
1455875	NM_000500.9(CYP21A2):c.1450C>T (p.Arg484Trp)	Pathogenic
1458325	NM_000500.9(CYP21A2):c.124C>T (p.Gln42Ter)	Pathogenic
1685686	NM_000500.9(CYP21A2):c.923del (p.Leu308fs)	Pathogenic
1687249	NM_000500.9(CYP21A2):c.433del (p.Gln145fs)	Pathogenic
189131	NM_000500.7:c.*28697972C>G	Pathogenic
189132	NM_000500.7:c.*28698317T>A	Pathogenic
189133	NM_000500.7:c.*28699001G>T	Pathogenic
189134	NM_000500.7:c.*28697405C>T	Pathogenic

SpliceAI

1626 predictions. Top by Δscore:

Variant	Effect	Δscore
6:32038622:AAG:A	donor_loss	1.0000
6:32038623:AGGTG:A	donor_loss	1.0000
6:32038624:GGTGA:G	donor_loss	1.0000
6:32038625:GTGAG:G	donor_loss	1.0000
6:32038626:T:A	donor_loss	1.0000
6:32038767:TCAAA:T	donor_gain	1.0000
6:32038812:G:GG	donor_gain	1.0000
6:32039244:GTGAG:G	donor_gain	1.0000
6:32039246:GAG:G	donor_gain	1.0000
6:32039247:AG:A	donor_gain	1.0000
6:32039248:GG:G	donor_gain	1.0000
6:32039249:G:GA	donor_loss	1.0000
6:32039249:G:GG	donor_gain	1.0000
6:32039354:A:AG	acceptor_gain	1.0000
6:32039354:AGC:A	acceptor_gain	1.0000
6:32039355:G:GA	acceptor_gain	1.0000
6:32039355:G:GC	acceptor_loss	1.0000
6:32039355:GC:G	acceptor_gain	1.0000
6:32039355:GCG:G	acceptor_gain	1.0000
6:32039355:GCGC:G	acceptor_gain	1.0000
6:32039355:GCGCA:G	acceptor_gain	1.0000
6:32039454:CAAGG:C	donor_loss	1.0000
6:32039455:AAGGT:A	donor_loss	1.0000
6:32039456:AG:A	donor_loss	1.0000
6:32039457:GG:G	donor_loss	1.0000
6:32039458:G:GA	donor_loss	1.0000
6:32039540:T:TA	acceptor_gain	1.0000
6:32039541:G:A	acceptor_gain	1.0000
6:32039542:GCA:G	acceptor_loss	1.0000
6:32039544:A:AG	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000183668 (6:32039720 C>T), RS1000419634 (6:32005219 A>G), RS1000516457 (6:32038438 C>T), RS1000789227 (6:32005688 C>T), RS1001862800 (6:32037287 G>A), RS1002049186 (6:32038139 AGTTGATGTG>A), RS1004184331 (6:32006783 T>G), RS1005387070 (6:32037657 C>T), RS1005419511 (6:32037242 T>C), RS1005488948 (6:32038856 T>A), RS1009263333 (6:32037820 C>G,T), RS1009644383 (6:32038222 A>G), RS1012736508 (6:32009170 C>A,G,T), RS1012768713 (6:32008216 G>A), RS1012991583 (6:32041558 T>G)

Disease associations

OMIM: gene MIM:613815 | disease phenotypes: MIM:130000, MIM:201710, MIM:606408, MIM:615963

GenCC curated gene-disease

Disease	Classification	Inheritance
classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	Definitive	Autosomal recessive
classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form	Supportive	Autosomal recessive
classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form	Supportive	Autosomal recessive

Mondo (8): Ehlers-Danlos syndrome (MONDO:0020066), congenital adrenal hyperplasia (MONDO:0018479), congenital lipoid adrenal hyperplasia due to STAR deficency (MONDO:0008725), Ehlers-Danlos syndrome due to tenascin-X deficiency (MONDO:0011670), vesicoureteral reflux 8 (MONDO:0014422), classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (MONDO:0008728), classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form (MONDO:0017839), classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form (MONDO:0017840)

Orphanet (5): Ehlers-Danlos syndrome (Orphanet:98249), Congenital adrenal hyperplasia (Orphanet:418), Congenital lipoid adrenal hyperplasia due to STAR deficency (Orphanet:90790), Classical-like Ehlers-Danlos syndrome type 1 (Orphanet:230839), Familial vesicoureteral reflux (Orphanet:289365)

HPO phenotypes

13 total (13 of 13 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000047	Hypospadias
HP:0000127	Renal salt wasting
HP:0000765	Abnormal thorax morphology
HP:0000771	Gynecomastia
HP:0000822	Hypertension
HP:0000840	Adrenogenital syndrome
HP:0001507	Growth abnormality
HP:0001943	Hypoglycemia
HP:0001945	Fever
HP:0001954	Recurrent fever
HP:0008221	Adrenal hyperplasia
HP:6000516	Elevated circulating 21-deoxycortisol concentration

GWAS associations

37 associations (top):

Study	Trait	p-value
GCST001942_21	Prostate cancer	5.000000e-09
GCST002627_2	Hypertension	4.000000e-11
GCST002630_2	Systolic blood pressure	3.000000e-09
GCST002631_6	Diastolic blood pressure	2.000000e-12
GCST002975_1	Postoperative atrial fibrillation in coronary artery bypass grafting surgery	3.000000e-06
GCST004131_25	Inflammatory bowel disease	2.000000e-31
GCST004133_79	Ulcerative colitis	5.000000e-65
GCST004521_114	Autism spectrum disorder or schizophrenia	3.000000e-17
GCST004521_117	Autism spectrum disorder or schizophrenia	3.000000e-15
GCST004521_118	Autism spectrum disorder or schizophrenia	3.000000e-15
GCST004521_126	Autism spectrum disorder or schizophrenia	2.000000e-10
GCST004521_154	Autism spectrum disorder or schizophrenia	3.000000e-08
GCST004521_17	Autism spectrum disorder or schizophrenia	2.000000e-12
GCST004521_170	Autism spectrum disorder or schizophrenia	4.000000e-14
GCST004521_173	Autism spectrum disorder or schizophrenia	4.000000e-14
GCST004521_209	Autism spectrum disorder or schizophrenia	5.000000e-16
GCST004521_211	Autism spectrum disorder or schizophrenia	5.000000e-15
GCST004521_213	Autism spectrum disorder or schizophrenia	5.000000e-13
GCST004521_227	Autism spectrum disorder or schizophrenia	4.000000e-12
GCST004521_296	Autism spectrum disorder or schizophrenia	6.000000e-18
GCST004521_45	Autism spectrum disorder or schizophrenia	2.000000e-16
GCST004521_81	Autism spectrum disorder or schizophrenia	1.000000e-14
GCST006190_17	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	4.000000e-10
GCST006190_18	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	7.000000e-06
GCST006190_58	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	1.000000e-10
GCST006190_59	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	1.000000e-09
GCST006192_37	Systolic blood pressure x smoking status (ever vs never) interaction (2df test)	3.000000e-14
GCST006192_87	Systolic blood pressure x smoking status (ever vs never) interaction (2df test)	4.000000e-11
GCST006193_49	Diastolic blood pressure x smoking status (current vs non-current) interaction (2df test)	6.000000e-09
GCST006193_87	Diastolic blood pressure x smoking status (current vs non-current) interaction (2df test)	3.000000e-09

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0006336	diastolic blood pressure
EFO:0006527	smoking status measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0009130	clostridium difficile infection

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D000312	Adrenal Hyperplasia, Congenital	C12.050.351.875.253.090.500; C12.200.706.316.090.500; C12.800.316.090.500; C16.131.939.316.129.500; C16.320.033; C16.320.565.925.249; C18.452.648.925.249; C19.053.440; C19.391.119.090.500
D004535	Ehlers-Danlos Syndrome	C14.907.454.240; C15.378.463.515.240; C16.131.831.428; C16.320.850.260; C17.300.200.310; C17.800.804.428; C17.800.827.260
C535979	Congenital adrenal hyperplasia due to 21 hydroxylase deficiency (supp.)
C536193	Ehlers-Danlos syndrome caused by tenascin-X deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2759 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

4 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 99,250 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL157101	KETOCONAZOLE	4	75,361
CHEMBL254328	ABIRATERONE	4	22,316
CHEMBL1921976	ORTERONEL	3	602
CHEMBL2105738	GALETERONE	3	971

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — CYP11, CYP17, CYP19, CYP20 and CYP21 families

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
abiraterone-C6 oxime	Inhibition	5.86	pIC50
(2S,4S)-ketoconazole	Inhibition	5.4	pIC50

Binding affinities (BindingDB)

7 measured of 7 human assays (7 total across all organisms); most potent 7 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
6-[(7S)-7-hydroxy-5,6-dihydropyrrolo[1,2-c]imidazol-7-yl]-N-methylnaphthalene-2-carboxamide	IC50	4 nM	US-9611270: Inhibitors of CYP17A1
(1S,2R,5S,10R,11S,15S)-2,15-dimethyl-14-(pyridin-3-yl)tetracyclo[8.7.0.0^{2,7}.0^{11,15}]heptadeca-7,13-dien-5-ol	IC50	29 nM	US-9487554: Estra-1,3,5(10),16-tetraene-3-carboxamide derivatives, processes for their preparation, pharmaceutical preparations comprising them and their use for preparing medicaments
(3S,8R,9S,10R,13S,14S)-3-hydroxy-10,13-dimethyl-17-pyridin-3-yl-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthrene-6-carboxamide	IC50	120 nM	US-9611270: Inhibitors of CYP17A1
(3S,5S,6E,8R,9S,10R,13S,14S)-6-hydroxyimino-10,13-dimethyl-17-pyridin-3-yl-1,2,3,4,5,7,8,9,11,12,14,15-dodecahydrocyclopenta[a]phenanthren-3-ol	IC50	150 nM	US-9611270: Inhibitors of CYP17A1
(3S,8R,9S,10R,13S,14S)-3-hydroxy-10,13-dimethyl-17-pyridin-3-yl-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthrene-6-carbonitrile	IC50	174 nM	US-9611270: Inhibitors of CYP17A1
(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-6-nitro-17-pyridin-3-yl-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-ol	IC50	183 nM	US-9611270: Inhibitors of CYP17A1
VN/124	IC50	282 nM	US-9611270: Inhibitors of CYP17A1

ChEMBL bioactivities

125 potent at pChembl≥5 of 127 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.15	IC50	0.7	nM	CHEMBL132778
8.40	IC50	4	nM	ORTERONEL
8.10	IC50	8	nM	CHEMBL3891718
8.10	IC50	8	nM	CHEMBL4210141
8.00	IC50	10	nM	CHEMBL4280255
7.70	IC50	20	nM	CHEMBL3980889
7.62	IC50	23.9	nM	CHEMBL4209941
7.58	IC50	26	nM	CHEMBL3968178
7.55	IC50	28	nM	CHEMBL3922888
7.49	IC50	32.4	nM	ABIRATERONE
7.38	IC50	42.1	nM	CHEMBL4210737
7.31	IC50	49	nM	CHEMBL3938615
7.29	IC50	51	nM	CHEMBL3894912
7.17	IC50	68	nM	CHEMBL4290805
7.14	IC50	73	nM	CHEMBL4284756
7.11	IC50	78	nM	CHEMBL3952032
7.11	IC50	77.2	nM	GALETERONE
7.07	IC50	85	nM	CHEMBL4279221
6.96	IC50	110	nM	CHEMBL4287608
6.91	IC50	123	nM	CHEMBL3931836
6.89	IC50	130	nM	CHEMBL4291856
6.83	IC50	148	nM	CHEMBL3960724
6.80	IC50	160	nM	CHEMBL4287787
6.78	IC50	166	nM	CHEMBL3964421
6.77	IC50	170	nM	CHEMBL4284316
6.72	IC50	190	nM	CHEMBL4127656
6.68	IC50	208	nM	CHEMBL4289930
6.63	IC50	234	nM	CHEMBL4213452
6.61	IC50	248	nM	GALETERONE
6.60	IC50	250	nM	CHEMBL4291002
6.58	IC50	262	nM	CHEMBL4283588
6.57	IC50	271	nM	CHEMBL3913908
6.56	IC50	273	nM	CHEMBL4283318
6.54	IC50	285	nM	CHEMBL4279727
6.53	IC50	296	nM	ABIRATERONE
6.50	IC50	316	nM	CHEMBL4128368
6.47	IC50	340	nM	CHEMBL4127385
6.41	IC50	393	nM	CHEMBL4126996
6.41	IC50	391	nM	CHEMBL4279058
6.38	IC50	416	nM	CHEMBL4128640
6.38	IC50	415	nM	CHEMBL4279441
6.37	IC50	430	nM	CHEMBL4129721
6.37	IC50	426	nM	CHEMBL4288383
6.36	IC50	440	nM	CHEMBL4209916
6.31	IC50	490	nM	CHEMBL4288457
6.28	IC50	520	nM	CHEMBL4288256
6.28	IC50	520	nM	CHEMBL4126284
6.27	IC50	537	nM	CHEMBL4209941
6.27	IC50	540	nM	CHEMBL4128449
6.25	IC50	565	nM	CHEMBL4127256

PubChem BioAssay actives

27 with measured affinity, of 48 total; 26 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(8R,9S,10R,13S,14S)-10,13-dimethyl-17-pyridin-3-yl-1,2,6,7,8,9,11,12,14,15-decahydrocyclopenta[a]phenanthren-3-one	1375970: Inhibition of C-terminal His-tagged recombinant human CYP21A2deltaH mutant expressed in Escherichia coli DH5alpha assessed as decrease in progesterone hydroxylation preincubated for 3 mins followed by NADPH addition measured after 10 mins in presence of cytochrome p450 reductase by LC-MS/MS method	ic50	0.0007	uM
1-[4-[[(2S,4R)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-4-(1-methylimidazol-2-yl)sulfonylpiperazine	1328451: Inhibition of recombinant CYP21 (unknown origin) overexpressed in human AD293 cells assessed as reduction in 11-deoxycortisol formation preincubated for 60 mins followed by addition of 17-alpha-hydroxyprogesterone as substrate measured after 45 mins by LC-MS/MS analysis	ic50	0.0080	uM
1-[4-[[(2S,4R)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-4-(methylsulfonylmethylsulfonyl)piperazine	1328451: Inhibition of recombinant CYP21 (unknown origin) overexpressed in human AD293 cells assessed as reduction in 11-deoxycortisol formation preincubated for 60 mins followed by addition of 17-alpha-hydroxyprogesterone as substrate measured after 45 mins by LC-MS/MS analysis	ic50	0.0200	uM
(3S,8R,9S,10R,13S,14S)-3-hydroxy-10,13-dimethyl-17-pyridin-3-yl-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthrene-6-carbonitrile	1375970: Inhibition of C-terminal His-tagged recombinant human CYP21A2deltaH mutant expressed in Escherichia coli DH5alpha assessed as decrease in progesterone hydroxylation preincubated for 3 mins followed by NADPH addition measured after 10 mins in presence of cytochrome p450 reductase by LC-MS/MS method	ic50	0.0239	uM
1-[4-[[(2S,4R)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-4-(difluoromethylsulfonyl)piperazine	1328451: Inhibition of recombinant CYP21 (unknown origin) overexpressed in human AD293 cells assessed as reduction in 11-deoxycortisol formation preincubated for 60 mins followed by addition of 17-alpha-hydroxyprogesterone as substrate measured after 45 mins by LC-MS/MS analysis	ic50	0.0260	uM
1-cyclopropylsulfonyl-4-[4-[[(2S,4R)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine	1328451: Inhibition of recombinant CYP21 (unknown origin) overexpressed in human AD293 cells assessed as reduction in 11-deoxycortisol formation preincubated for 60 mins followed by addition of 17-alpha-hydroxyprogesterone as substrate measured after 45 mins by LC-MS/MS analysis	ic50	0.0280	uM
Abiraterone	1375970: Inhibition of C-terminal His-tagged recombinant human CYP21A2deltaH mutant expressed in Escherichia coli DH5alpha assessed as decrease in progesterone hydroxylation preincubated for 3 mins followed by NADPH addition measured after 10 mins in presence of cytochrome p450 reductase by LC-MS/MS method	ic50	0.0324	uM
(1S,2R,5S,7R,9R,11R,12S,16S)-2,16-dimethyl-15-pyridin-3-ylpentacyclo[9.7.0.02,7.07,9.012,16]octadec-14-en-5-ol	1375970: Inhibition of C-terminal His-tagged recombinant human CYP21A2deltaH mutant expressed in Escherichia coli DH5alpha assessed as decrease in progesterone hydroxylation preincubated for 3 mins followed by NADPH addition measured after 10 mins in presence of cytochrome p450 reductase by LC-MS/MS method	ic50	0.0421	uM
1-[4-[[(2S,4R)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-4-(trifluoromethylsulfonyl)piperazine	1328451: Inhibition of recombinant CYP21 (unknown origin) overexpressed in human AD293 cells assessed as reduction in 11-deoxycortisol formation preincubated for 60 mins followed by addition of 17-alpha-hydroxyprogesterone as substrate measured after 45 mins by LC-MS/MS analysis	ic50	0.0490	uM
1-[4-[[(2S,4R)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-4-propan-2-ylsulfonylpiperazine	1328451: Inhibition of recombinant CYP21 (unknown origin) overexpressed in human AD293 cells assessed as reduction in 11-deoxycortisol formation preincubated for 60 mins followed by addition of 17-alpha-hydroxyprogesterone as substrate measured after 45 mins by LC-MS/MS analysis	ic50	0.0510	uM
(3S,8R,9S,10R,13S,14S)-17-(benzimidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-ol	1375970: Inhibition of C-terminal His-tagged recombinant human CYP21A2deltaH mutant expressed in Escherichia coli DH5alpha assessed as decrease in progesterone hydroxylation preincubated for 3 mins followed by NADPH addition measured after 10 mins in presence of cytochrome p450 reductase by LC-MS/MS method	ic50	0.0772	uM
2-[4-[4-[[(2S,4R)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]sulfonylacetonitrile	1328451: Inhibition of recombinant CYP21 (unknown origin) overexpressed in human AD293 cells assessed as reduction in 11-deoxycortisol formation preincubated for 60 mins followed by addition of 17-alpha-hydroxyprogesterone as substrate measured after 45 mins by LC-MS/MS analysis	ic50	0.0780	uM
1-[4-[[(2S,4R)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-4-(oxan-4-ylsulfonyl)piperazine	1328451: Inhibition of recombinant CYP21 (unknown origin) overexpressed in human AD293 cells assessed as reduction in 11-deoxycortisol formation preincubated for 60 mins followed by addition of 17-alpha-hydroxyprogesterone as substrate measured after 45 mins by LC-MS/MS analysis	ic50	0.1230	uM
1-[4-[[(2S,4R)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-4-thiophen-2-ylsulfonylpiperazine	1328451: Inhibition of recombinant CYP21 (unknown origin) overexpressed in human AD293 cells assessed as reduction in 11-deoxycortisol formation preincubated for 60 mins followed by addition of 17-alpha-hydroxyprogesterone as substrate measured after 45 mins by LC-MS/MS analysis	ic50	0.1480	uM
1-[4-[[(2S,4R)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-4-(2-methoxyethylsulfonyl)piperazine	1328451: Inhibition of recombinant CYP21 (unknown origin) overexpressed in human AD293 cells assessed as reduction in 11-deoxycortisol formation preincubated for 60 mins followed by addition of 17-alpha-hydroxyprogesterone as substrate measured after 45 mins by LC-MS/MS analysis	ic50	0.1660	uM
(3S,5S,6S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-pyridin-3-yl-2,3,4,5,6,7,8,9,11,12,14,15-dodecahydro-1H-cyclopenta[a]phenanthrene-3,6-diol	1375970: Inhibition of C-terminal His-tagged recombinant human CYP21A2deltaH mutant expressed in Escherichia coli DH5alpha assessed as decrease in progesterone hydroxylation preincubated for 3 mins followed by NADPH addition measured after 10 mins in presence of cytochrome p450 reductase by LC-MS/MS method	ic50	0.2340	uM
1-[4-[[(2S,4R)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-4-ethylsulfonylpiperazine	1328451: Inhibition of recombinant CYP21 (unknown origin) overexpressed in human AD293 cells assessed as reduction in 11-deoxycortisol formation preincubated for 60 mins followed by addition of 17-alpha-hydroxyprogesterone as substrate measured after 45 mins by LC-MS/MS analysis	ic50	0.2710	uM
(3S,5S,8R,9S,10R,13S,14S)-3-hydroxy-10,13-dimethyl-17-pyridin-3-yl-1,2,3,4,5,7,8,9,11,12,14,15-dodecahydrocyclopenta[a]phenanthren-6-one	1375970: Inhibition of C-terminal His-tagged recombinant human CYP21A2deltaH mutant expressed in Escherichia coli DH5alpha assessed as decrease in progesterone hydroxylation preincubated for 3 mins followed by NADPH addition measured after 10 mins in presence of cytochrome p450 reductase by LC-MS/MS method	ic50	0.4400	uM
(3S,8R,9S,10R,13S,14S)-3-hydroxy-10,13-dimethyl-17-pyridin-3-yl-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthrene-6-carboxamide	1375970: Inhibition of C-terminal His-tagged recombinant human CYP21A2deltaH mutant expressed in Escherichia coli DH5alpha assessed as decrease in progesterone hydroxylation preincubated for 3 mins followed by NADPH addition measured after 10 mins in presence of cytochrome p450 reductase by LC-MS/MS method	ic50	0.6730	uM
(3S,8R,10R,13S)-10,13-dimethyl-17-pyridin-3-yl-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-ol	1286718: Inhibition of CYP21A2 in human H295R cells using hydroxy progesterone as substrate incubated for 120 mins by LC-MS method	ic50	1.0500	uM
(3S,5S,6Z,8R,9S,10R,13S,14S)-6-hydroxyimino-10,13-dimethyl-17-pyridin-3-yl-1,2,3,4,5,7,8,9,11,12,14,15-dodecahydrocyclopenta[a]phenanthren-3-ol	1375970: Inhibition of C-terminal His-tagged recombinant human CYP21A2deltaH mutant expressed in Escherichia coli DH5alpha assessed as decrease in progesterone hydroxylation preincubated for 3 mins followed by NADPH addition measured after 10 mins in presence of cytochrome p450 reductase by LC-MS/MS method	ic50	1.3900	uM
1-[4-[[(2S,4R)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-4-methylsulfonylpiperazine	1328451: Inhibition of recombinant CYP21 (unknown origin) overexpressed in human AD293 cells assessed as reduction in 11-deoxycortisol formation preincubated for 60 mins followed by addition of 17-alpha-hydroxyprogesterone as substrate measured after 45 mins by LC-MS/MS analysis	ic50	1.6000	uM
(1S,2R,5S,7S,11S,12S,16S)-5-hydroxy-2,16-dimethyl-15-pyridin-3-yl-8-azatetracyclo[9.7.0.02,7.012,16]octadec-14-en-9-one	1375970: Inhibition of C-terminal His-tagged recombinant human CYP21A2deltaH mutant expressed in Escherichia coli DH5alpha assessed as decrease in progesterone hydroxylation preincubated for 3 mins followed by NADPH addition measured after 10 mins in presence of cytochrome p450 reductase by LC-MS/MS method	ic50	3.6050	uM
1-[4-[4-[[2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]ethanone	1328451: Inhibition of recombinant CYP21 (unknown origin) overexpressed in human AD293 cells assessed as reduction in 11-deoxycortisol formation preincubated for 60 mins followed by addition of 17-alpha-hydroxyprogesterone as substrate measured after 45 mins by LC-MS/MS analysis	ic50	4.3000	uM
1-[4-[4-[[(2S,4S)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]ethanone	161641: Inhibition of Progesterone 21-hydroxylase cytochrome P450 21	ic50	4.4600	uM
1-[4-[4-[[(2R,4R)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]ethanone	161641: Inhibition of Progesterone 21-hydroxylase cytochrome P450 21	ic50	6.5700	uM

CTD chemical–gene interactions

73 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Colforsin	decreases reaction, increases expression, affects cotreatment, decreases expression	8
Benzo(a)pyrene	increases mutagenesis, affects cotreatment, decreases methylation, increases expression, increases methylation	4
Progesterone	increases hydroxylation, increases chemical synthesis, increases metabolic processing, affects cotreatment, decreases chemical synthesis (+2 more)	3
Valproic Acid	increases expression, decreases expression, decreases reaction	3
8-Bromo Cyclic Adenosine Monophosphate	increases expression, decreases reaction	3
3,4,5,3’,4’-pentachlorobiphenyl	increases expression, increases activity	2
Resveratrol	affects cotreatment, decreases expression	2
Acetaminophen	decreases expression	2
Ketoconazole	decreases expression, increases activity, increases chemical synthesis, affects cotreatment	2
Mitotane	decreases reaction, increases expression, decreases expression	2
aristolochic acid I	increases expression	1
fluorene-9-bisphenol	decreases reaction, increases expression	1
triptolide	affects cotreatment, decreases expression	1
perflubron	increases expression	1
2,4,6-tribromophenol	decreases expression	1
daidzein	decreases reaction, increases expression	1
pirinixic acid	increases activity, increases expression, affects binding	1
deoxynivalenol	increases expression	1
4,4’-bisphenol F	decreases expression	1
physcione	increases hydroxylation	1
2,4,5,2’,5’-pentachlorobiphenyl	increases expression	1
tributyltin	decreases expression	1
HT-2 toxin	increases expression	1
tris(2-butoxyethyl) phosphate	decreases expression	1
2-acetyltributylcitrate	increases expression	1
cypermethrin	decreases expression	1
tetrabromobisphenol A	increases expression	1
triphenyltin	decreases expression	1
1-nitropyrene	decreases expression	1
3,3’,4,4’,5,5’-hexabromobiphenyl	increases expression	1

ChEMBL screening assays

15 unique, capped per target: 10 binding, 5 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3583945	Binding	Inhibition of human CYP21 expressed in COS7 cells incubated for 1 hr before 17-hydroxypregnenolone substrate addition by HTRF-based assay	Discovery of Benzimidazole CYP11B2 Inhibitors with in Vivo Activity in Rhesus Monkeys. — ACS Med Chem Lett
CHEMBL3784034	ADMET	Inhibition of CYP21A2 in human H295R cells using hydroxy progesterone as substrate incubated for 120 mins by LC-MS method	Discovery of the Selective CYP17A1 Lyase Inhibitor BMS-351 for the Treatment of Prostate Cancer. — ACS Med Chem Lett

Cellosaurus cell lines

9 cell lines: 8 transformed cell line, 1 finite cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_EJ64	GM14732	Transformed cell line	Female
CVCL_EJ65	GM14733	Transformed cell line	Male
CVCL_GZ39	GM02241	Finite cell line	Female
CVCL_GZ40	GM02242	Transformed cell line	Female
CVCL_GZ42	GM11781	Transformed cell line	Female
CVCL_GZ43	GM12217	Transformed cell line	Male
CVCL_GZ50	GM14734	Transformed cell line	Male
CVCL_VC47	DD1463	Transformed cell line	Male
CVCL_VC48	DD1464	Transformed cell line	Female

Clinical trials (associated diseases)

134 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04890431	PHASE4	UNKNOWN	Impact of Oxygen Therapy on Fatigue in Patients With Hypermobile-type Ehlers-Danlos Syndrome
NCT05603741	PHASE4	ACTIVE_NOT_RECRUITING	Local Anesthetic Response in Ehlers-Danlos Syndrome (EDS) and Healthy Volunteers
NCT03760835	PHASE4	RECRUITING	Congenital Adrenal Hyperplasia Once Daily Hydrocortisone Treatment
NCT04536662	PHASE4	UNKNOWN	Comparisons of Different Forms of Glucocorticoid on the Recovery of Reproductive Function in Patients With 21α-hydroxylase Deficiency
NCT05279937	PHASE3	NOT_YET_RECRUITING	The Ultrasound-Guided Dextrose Prolotherapy in Ehlers-Danlos Syndrome Patients
NCT00001521	PHASE3	COMPLETED	Three Drug Combination Therapy Versus Conventional Treatment of Children With Congenital Adrenal Hyperplasia
NCT02716818	PHASE3	COMPLETED	Comparison of Chronocort® With Standard Glucocorticoid Therapy in Patients With Congenital Adrenal Hyperplasia
NCT03062280	PHASE3	COMPLETED	A Study of the Efficacy, Safety and Tolerability of Chronocort in Treating CAH
NCT03532022	PHASE3	WITHDRAWN	Open-label Comparison of Chronocort® Versus Standard Glucocorticoid Replacement Therapy
NCT04490915	PHASE3	ACTIVE_NOT_RECRUITING	Global Safety and Efficacy Registration Study of Crinecerfont for Congenital Adrenal Hyperplasia
NCT04806451	PHASE3	ACTIVE_NOT_RECRUITING	Global Safety and Efficacy Registration Study of Crinecerfont in Pediatric Participants With Classic Congenital Adrenal Hyperplasia (CAHtalyst Pediatric Study)
NCT05063994	PHASE3	COMPLETED	Comparison of Chronocort Versus Standard Hydrocortisone Replacement Therapy in Participants Aged 16 Years and Over With Congenital Adrenal Hyperplasia
NCT05299554	PHASE3	COMPLETED	Long-term Safety Study of Chronocort in the Treatment of Participants With Congenital Adrenal Hyperplasia
NCT07144163	PHASE3	RECRUITING	A Study to Evaluate Atumelnant in Adults With Congenital Adrenal Hyperplasia
NCT05128942	PHASE2	TERMINATED	A Phase 2 Study to Evaluate the Safety, Efficacy and PK of Tildacerfont in Children Aged 2-17 Years With CAH
NCT00001966	PHASE2	COMPLETED	Mind-Body Therapy for Pain in Ehlers-Danlos Syndrome
NCT00621985	PHASE2	COMPLETED	Dexamethasone Treatment of Congenital Adrenal Hyperplasia
NCT01735617	PHASE2	COMPLETED	Pilot Study to Characterize and Examine the Pharmacokinetics and Efficacy of Chronocort® in Adults With CAH
NCT01771328	PHASE2	UNKNOWN	Continuous Subcutaneous Hydrocortisone Infusion in Congenital Adrenal Hyperplasia
NCT01859312	PHASE2	COMPLETED	Comparison of Cortisol Pump With Standard Treatment for Congenital Adrenal Hyperplasia
NCT02804178	PHASE2	COMPLETED	A Study of ATR-101 for the Treatment of Congenital Adrenal Hyperplasia
NCT03257462	PHASE2	COMPLETED	Study of SPR001 in Adults With Classic Congenital Adrenal Hyperplasia
NCT03548246	PHASE2	WITHDRAWN	Androgen Reduction in Congenital Adrenal Hyperplasia
NCT03669549	PHASE2	TERMINATED	Nevanimibe HCl for the Treatment of Classic CAH
NCT03687242	PHASE2	COMPLETED	Study to Evaluate the Safety and Efficacy of SPR001 in Subjects With Classic Congenital Adrenal Hyperplasia
NCT04457336	PHASE2	TERMINATED	A Ph2b to Evaluate Clinical Efficacy and Safety of Tildacerfont in Adult CAH
NCT04544410	PHASE2	TERMINATED	A Ph2b to Evaluate Tildacerfont in the Reduction of Glucocorticoid Steroid Doses in Adult CAH
NCT05907291	PHASE2	COMPLETED	Evaluate the Safety, Efficacy, and Pharmacokinetics of CRN04894 in Participants With Congenital Adrenal Hyperplasia (TouCAHn)
NCT06712823	PHASE2	RECRUITING	An Extension Study to Evaluate Safety and Efficacy in Participants Treated With CRN04894
NCT07187375	PHASE2	RECRUITING	Pharmacokinetics, Safety and Tolerability of Crinecerfont in Participants With Congenital Adrenal Hyperplasia Who Are Less Than 2 Years Old
NCT07536269	PHASE2	NOT_YET_RECRUITING	Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Crinecerfont in Participants With Classic Congenital Adrenal Hyperplasia (CAH) Who Are Less Than 4 Years Old
NCT01495910	PHASE1	COMPLETED	A Study Examining Doses of Abiraterone Acetate in Adult Women With 21-Hydroxylase Deficiency
NCT02349503	PHASE1	WITHDRAWN	Safety, Pharmacokinetics and Pharmacodynamics of NBI-77860 in Adolescent Females With Congenital Adrenal Hyperplasia
NCT02574910	PHASE1	TERMINATED	Androgen Reduction in Congenital Adrenal Hyperplasia, Phase 1
NCT03019614	PHASE1	COMPLETED	An Open Label Study in Healthy Volunteers to Compare Chronocort® to Hydrocortisone
NCT03051893	PHASE1	COMPLETED	A Two-part, Study to Compare the Pharmacokinetics and Dose Proportionality of up to 6 Chronocort Formulations
NCT03718234	PHASE1	COMPLETED	Subcutaneous Hydrocortisone Children With Congenital Adrenal Hyperplasia
NCT00519818	PHASE1/PHASE2	COMPLETED	Comparison of Two Forms of Hydrocortisone in Patients With Congenital Adrenal Hyperplasia
NCT00542841	Not specified	COMPLETED	Examining Genetic Differences Among People With 21-Hydroxylase Deficiency
NCT01862380	Not specified	UNKNOWN	Adrenocortical Functions in Women With Nonclassical 21-hydroxylase Deficiency.