21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia: genes and variants
21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia is linked to 1 analyzed protein (CYP21A2). 37 DNA variants are known to cause it; 53 more are uncertain, and 1 of those already look disease-causing on computable evidence.
Last updated 2026-09-30. Research information, not medical advice.
Genes linked to 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia
CYP21A2: Steroid 21-hydroxylase
It enables cortisol and aldosterone synthesis by 21-hydroxylating adrenal steroid precursors. Biallelic loss-of-function variants cause congenital adrenal hyperplasia, with cortisol deficiency, androgen excess, and in severe forms life-threatening salt wasting.
37 disease-causing and 52 uncertain variants in CYP21A2 are linked to 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia.
Weakly linked (only a few uncertain records): CYP19A1.
Known disease-causing variants in 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| CYP21A2 G425S | 425 | Disease-causing (★★) | |
| CYP21A2 P31L | 31 | Disease-causing (★★) | |
| CYP21A2 I237N | 237 | Disease-causing (★★) | |
| CYP21A2 V238E | 238 | Disease-causing (★★) | |
| CYP21A2 M240K | 240 | Disease-causing (★★) | |
| CYP21A2 R427C | 427 | Disease-causing (★★) | |
| CYP21A2 G57R | 57 | Disease-causing (★★) | |
| CYP21A2 R92G | 92 | Disease-causing (★★) | |
| CYP21A2 S114F | 114 | Disease-causing (★★) | |
| CYP21A2 M284V | 284 | Disease-causing (★★) | |
| CYP21A2 R342W | 342 | Disease-causing (★★) | |
| CYP21A2 R357W | 357 | Disease-causing (★★) | |
| CYP21A2 R370W | 370 | Disease-causing (★★) | |
| CYP21A2 S373N | 373 | Disease-causing (★★) | |
| CYP21A2 R409C | 409 | Disease-causing (★★) | |
| CYP21A2 P454S | 454 | Disease-causing (★★) | |
| CYP21A2 G425V | 425 | Disease-causing (★) | |
| CYP21A2 P31S | 31 | Disease-causing (★) | |
| CYP21A2 L434P | 434 | Disease-causing (★) | |
| CYP21A2 E432K | 432 | Disease-causing (★) | |
| CYP21A2 S166C | 166 | Disease-causing (★) | |
| CYP21A2 S302Y | 302 | Disease-causing (★) | |
| CYP21A2 A348T | 348 | Disease-causing (★) | |
| CYP21A2 A363V | 363 | Disease-causing (★) | |
| CYP21A2 I379N | 379 | Disease-causing (★) | |
| CYP21A2 R340H | 340 | Disease-causing (★) | |
| CYP21A2 R355C | 355 | Disease-causing (★) | |
| CYP21A2 M261R | 261 | Disease-causing | |
| CYP21A2 G431S | 431 | Disease-causing | |
| CYP21A2 M261T | 261 | Disease-causing | |
| CYP21A2 L52V | 52 | Disease-causing | |
| CYP21A2 P106L | 106 | Disease-causing | |
| CYP21A2 C170Y | 170 | Disease-causing | |
| CYP21A2 L187V | 187 | Disease-causing | |
| CYP21A2 G252S | 252 | Disease-causing | |
| CYP21A2 V282L | 282 | Disease-causing | |
| CYP21A2 R484P | 484 | Disease-causing |
Uncertain variants in 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia that look disease-causing
| Variant | Position | Protein part | Clinical label | Evidence |
|---|---|---|---|---|
| CYP21A2 R355P | 355 | Uncertain (★) | +6: 2 other pathogenic changes within 3 positions; R355C at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.68 |
Which prediction tools work for 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia
How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).
- PolyPhen-2: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CATVariant: 87 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- phyloP: 87 out of 100
- SIFT: 87 out of 100
- CADD: 82 out of 100
Same protein, different disease
- Congenital adrenal hyperplasia is also caused by CYP21A2 variants; they fall in the same places as the 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia variants (16 disease-causing).
Diseases related to 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia
- Congenital adrenal hyperplasia, also linked to CYP21A2
Frequently asked questions
Which genes are linked to 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia?
In CATVariant, 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia is linked to 1 analyzed protein: CYP21A2 (Steroid 21-hydroxylase).
How many genetic variants are linked to 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia?
95 variants: 37 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 53 are of uncertain significance or have conflicting reports.
Which uncertain variants in 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia look disease-causing?
1 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example CYP21A2 R355P. These are leads for expert review, not diagnoses.
Which variant effect predictor works best for 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia?
Among tools not trained on clinical labels, phyloP separates this disease's known disease-causing variants from harmless ones best (AUROC 0.87, based on 31 disease-causing and 12 harmless variants).
About this data
Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.
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