CYP21A2

Chr 6AR

cytochrome P450 family 21 subfamily A member 2

Also known as: CA21H, CAH1, CPS1, CYP21, CYP21B, P450c21B

NCBI Gene: 1589ENSG00000231852UniProt: P08686

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. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Adrenal hyperplasia, congenital, due to 21-hydroxylase deficiencyMIM #201910
AR
Hyperandrogenism, nonclassic type, due to 21-hydroxylase deficiencyMIM #201910
AR
435
ClinVar variants
152
Pathogenic / LP
0.00
pLI score
4
Active trials
Clinical Summary— CYP21A2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
152 Pathogenic / Likely Pathogenic· 153 VUS of 435 total submissions
💊
Clinical Trials
4 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.82LOEUF
pLI 0.000
Z-score 2.16
OE 0.47 (0.28–0.82)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.15Z-score
OE missense 0.80 (0.72–0.90)
219 obs / 272.6 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.47 (0.28–0.82)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.80 (0.72–0.90)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.84
0≤1.21.6
LoF obs/exp: 9 / 19.2Missense obs/exp: 219 / 272.6Syn Z: 1.37

ClinVar Variant Classifications

435 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic81
Likely Pathogenic71
VUS153
Likely Benign46
Benign55
Conflicting29
81
Pathogenic
71
Likely Pathogenic
153
VUS
46
Likely Benign
55
Benign
29
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
16
30
35
0
81
Likely Pathogenic
17
38
15
1
71
VUS
3
108
38
4
153
Likely Benign
0
4
30
12
46
Benign
0
3
41
11
55
Conflicting
—29
Total3618315928435

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

CYP21A2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Adrenal hyperplasia, congenital, due to 21-hydroxylase deficiency

MIM #201910

Molecular basis of disorder known

Autosomal recessive

Hyperandrogenism, nonclassic type, due to 21-hydroxylase deficiency

MIM #201910

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — CYP21A2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Congenital Adrenal Hyperplasia-Current Insights in Pathophysiology, Diagnostics, and Management.
Claahsen-van der Grinten HL et al.·Endocr Rev
2022Review
Congenital Adrenal Hyperplasia.
Witchel SF·J Pediatr Adolesc Gynecol
2017Review
CYP21A2 mutation update: Comprehensive analysis of databases and published genetic variants.
Simonetti L et al.·Hum Mutat
2018Review
The Genetics of Female and Male Infertility.
Tüttelmann F et al.·Dtsch Arztebl Int
2025Review
Genotype-phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency.
New MI et al.·Proc Natl Acad Sci U S A
2013
Structure-phenotype correlations of human CYP21A2 mutations in congenital adrenal hyperplasia.
Haider S et al.·Proc Natl Acad Sci U S A
2013
Nonclassic adrenal hyperplasia.
Speiser PW·Rev Endocr Metab Disord
2009Review
CYP21A2 intronic variants causing 21-hydroxylase deficiency.
Concolino P et al.·Metabolism
2017Review
Congenital Adrenal Hyperplasia and Ehlers-Danlos Syndrome.
Marino R et al.·Front Endocrinol (Lausanne)
2022Review
CAH-X Syndrome: Genetic and Clinical Profile.
Concolino P et al.·Mol Diagn Ther
2022Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Genetic diagnosis of CYP21A2-related CAH: adaptive sampling long-read sequencing is an accurate and scalable solution.
Lildballe DL et al.·Eur J Hum Genet
2026
Transcript Patterns of Bovine CYP21A2 and Its Pseudogene in Adrenal and Ovarian Tissues.
Wozniak J et al.·Genes (Basel)
2025🔓 Open Access
[Prenatal genetic analysis of a fetus with 21-hydroxylase deficiency due to compound heterozygous variants of CYP21A2 gene].
Zhang W et al.·Zhonghua Yi Xue Yi Chuan Xue Za Zhi
2025
Accurate diagnosis of congenital adrenal hyperplasia due to CYP21A2 variants requires promoter analysis.
Schernthaner-Reiter MH et al.·Eur J Endocrinol
2025
Optimized Homologous Sequence Alignment for the Identification of CYP21A2 Variants in 21-Hydroxylase Deficiency Using Next-Generation Sequencing Technology.
Chen Y et al.·Risk Manag Healthc Policy
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Congenital Adrenal Hyperplasia

A Study of Gene Therapy for Classic Congenital Adrenal Hyperplasia (CAH)

ACTIVE NOT RECRUITING
NCT04783181Phase PHASE1, PHASE2Adrenas Therapeutics IncStarted 2021-07-01
AAV BBP-631
Hyperandrogenism

Combined Use of Machine Learning and Metabolomics to Improve the Diagnosis and Management of Hyperandrogenism

NOT YET RECRUITING
NCT07253454Assistance Publique - Hôpitaux de ParisStarted 2026-01
data collection
Variant Nucleotide

Solving Challenging Diagnoses Through Ultra-long Read Sequencing

ACTIVE NOT RECRUITING
NCT06775613Phase NAIRCCS Azienda Ospedaliero-Universitaria di BolognaStarted 2023-03-10
Long-read sequencing
CAH - 21-Hydroxylase Deficiency

Parenting and CAH - 21-hydroxylase Deficiency

NOT YET RECRUITING
NCT06900153Assistance Publique - Hôpitaux de ParisStarted 2025-12
phone questionnaire

External Resources

Links to major genomics databases and tools