Differences in sex development: genes and variants

Genes linked to Differences in sex development

• AR: Androgen receptor

  Androgen binding redirects its transcriptional program to control male sexual differentiation, reproductive physiology, muscle and bone biology, and other androgen-responsive processes. Loss-of-function variants cause androgen insensitivity, CAG expansion causes spinal and bulbar muscular atrophy, and persistent signaling drives prostate cancer.

  9 disease-causing and 0 uncertain variants in AR are linked to Differences in sex development.

• SRD5A2: 3-oxo-5-alpha-steroid 4-dehydrogenase 2

  It converts testosterone to the more potent androgen dihydrotestosterone in androgen-responsive tissues. Biallelic loss-of-function variants cause 5-alpha-reductase type 2 deficiency, leading to undervirilization of 46,XY individuals and often increased virilization at puberty.

  5 disease-causing and 1 uncertain variants in SRD5A2 are linked to Differences in sex development.

• HSD17B3: 17-beta-hydroxysteroid dehydrogenase type 3

  It converts androstenedione to testosterone in the testes, providing a key step in androgen synthesis during male sexual development. Biallelic loss-of-function variants cause 17-beta-hydroxysteroid dehydrogenase 3 deficiency, a 46,XY disorder of sex development.

  2 disease-causing and 1 uncertain variants in HSD17B3 are linked to Differences in sex development.

• CYP17A1: Steroid 17-alpha-hydroxylase/17,20 lyase

  Its 17-alpha-hydroxylase and 17,20-lyase activities direct adrenal and gonadal steroid synthesis toward glucocorticoids and sex steroids. Biallelic deficiency causes 17-alpha-hydroxylase/17,20-lyase deficiency with hypertension, hypokalemia, and impaired sexual development.

  2 disease-causing and 0 uncertain variants in CYP17A1 are linked to Differences in sex development.

• AMH: Anti-Muellerian hormone

  During male fetal development, it drives regression of the Mullerian ducts and therefore prevents formation of female internal reproductive structures. Loss of AMH signaling can cause persistent Mullerian duct syndrome in otherwise virilized 46,XY individuals.

  1 disease-causing and 3 uncertain variants in AMH are linked to Differences in sex development.

• CYP11B1: Cytochrome P450 11B1, mitochondrial

  It catalyzes the final step of cortisol synthesis and also contributes to adrenal steroid metabolism. Biallelic loss-of-function variants cause 11-beta-hydroxylase-deficient congenital adrenal hyperplasia, characterized by cortisol deficiency, androgen excess, and frequently hypertension.

  1 disease-causing and 1 uncertain variants in CYP11B1 are linked to Differences in sex development.

• POR: NADPH--cytochrome P450 reductase

  It transfers electrons from NADPH to microsomal cytochrome P450 enzymes, making it essential for steroid synthesis and metabolism of many drugs and xenobiotics. Biallelic pathogenic variants cause P450 oxidoreductase deficiency, with disordered steroidogenesis and skeletal abnormalities.

  1 disease-causing and 1 uncertain variants in POR are linked to Differences in sex development.

• CYP19A1: Aromatase

  It converts androgens to estrogens and is therefore essential for estrogen biosynthesis in gonads, adipose tissue, placenta, and other sites. Loss-of-function variants cause aromatase deficiency, whereas excessive activity can contribute to estrogen excess; aromatase inhibition is central to treatment of many breast cancers.

  1 disease-causing and 0 uncertain variants in CYP19A1 are linked to Differences in sex development.

Weakly linked (only a few uncertain records): FGFR1 and HSD3B2.

Where Differences in sex development variants cluster

• AR Interaction with LPXN (positions 552–919): 8 of 9 disease-causing changes, 2.2× more than its size predicts.

Known disease-causing variants in Differences in sex development

Which prediction tools work for Differences in sex development

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• PolyPhen-2: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 92 out of 100
• CATVariant: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 90 out of 100
• SIFT: 86 out of 100
• MetaLR: 85 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 74 out of 100

Same protein, different disease

• Androgen resistance syndrome is also caused by AR variants; they fall mostly in different places as the Differences in sex development variants (85 disease-causing).
• Kennedy disease is also caused by AR variants; they fall mostly in different places as the Differences in sex development variants (46 disease-causing).
• Male infertility is also caused by AR variants; they fall mostly in different places as the Differences in sex development variants (7 disease-causing).
• Partial androgen insensitivity syndrome is also caused by AR variants; they fall mostly in different places as the Differences in sex development variants (7 disease-causing).
• Ovarian cancer is also caused by AR variants; they fall mostly in different places as the Differences in sex development variants (4 disease-causing).
• 3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency is also caused by SRD5A2 variants; they fall mostly in different places as the Differences in sex development variants (43 disease-causing).
• Testosterone 17-beta-dehydrogenase deficiency is also caused by HSD17B3 variants; they fall mostly in different places as the Differences in sex development variants (20 disease-causing).
• Deficiency of steroid 17-alpha-monooxygenase is also caused by CYP17A1 variants; they fall mostly in different places as the Differences in sex development variants (40 disease-causing).
• Congenital adrenal hyperplasia is also caused by CYP17A1 variants; they fall mostly in different places as the Differences in sex development variants (13 disease-causing).
• 17-alpha-hydroxylase/17,20-lyase deficiency, combined complete is also caused by CYP17A1 variants; they fall mostly in different places as the Differences in sex development variants (3 disease-causing).
• Persistent Mullerian duct syndrome is also caused by AMH variants; they fall mostly in different places as the Differences in sex development variants (4 disease-causing).
• Deficiency of steroid 11-beta-monooxygenase is also caused by CYP11B1 variants; they fall mostly in different places as the Differences in sex development variants (33 disease-causing).
• Glucocorticoid-remediable aldosteronism is also caused by CYP11B1 variants; they fall mostly in different places as the Differences in sex development variants (20 disease-causing).
• Congenital adrenal hyperplasia is also caused by CYP11B1 variants; they fall mostly in different places as the Differences in sex development variants (10 disease-causing).

Diseases related to Differences in sex development

• Congenital adrenal hyperplasia, also linked to CYP11B1, CYP17A1 and POR
• Prostate cancer, also linked to AR, CYP17A1 and SRD5A2
• Disorder of sexual differentiation, also linked to AR and HSD17B3
• Androgen resistance syndrome, also linked to AR
• Kennedy disease, also linked to AR
• Ovarian cancer, also linked to AR
• 3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency, also linked to SRD5A2
• Deficiency of steroid 17-alpha-monooxygenase, also linked to CYP17A1
• Deficiency of steroid 11-beta-monooxygenase, also linked to CYP11B1
• Glucocorticoid-remediable aldosteronism, also linked to CYP11B1
• Testosterone 17-beta-dehydrogenase deficiency, also linked to HSD17B3
• Aromatase deficiency, also linked to CYP19A1

Frequently asked questions

Which genes are linked to Differences in sex development?

In CATVariant, Differences in sex development is linked to 8 analyzed proteins: AR (Androgen receptor), SRD5A2 (3-oxo-5-alpha-steroid 4-dehydrogenase 2), HSD17B3 (17-beta-hydroxysteroid dehydrogenase type 3), CYP17A1 (Steroid 17-alpha-hydroxylase/17,20 lyase), AMH (Anti-Muellerian hormone), CYP11B1 (Cytochrome P450 11B1, mitochondrial) and 2 more.

How many genetic variants are linked to Differences in sex development?

31 variants: 22 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 9 are of uncertain significance or have conflicting reports.

Which uncertain variants in Differences in sex development look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Differences in sex development?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.93, based on 8 disease-causing and 30 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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