46,XY disorder of sex development due to testicular 17,20-desmolase deficiency

Summary

46,XY disorder of sex development due to testicular 17,20-desmolase deficiency (MONDO:0013664) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 11

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	46,XY disorder of sex development due to testicular 17,20-desmolase deficiency
Mondo ID	MONDO:0013664
MeSH	C564109
OMIM	614279
Orphanet	443087
DOID	DOID:0111773
SNOMED CT	49013001
UMLS	C1839840
MedGen	333416
GARD	0017752
Is cancer (heuristic)	no

Also known as: 46,XY sex reversal 8 · 46,XY sex reversal type 8 · 46XY sex reversal 8 · 46XY sex reversal 8, modifier of · SRXY8

Data availability: 11 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › reproductive system disorder › gonadal disorder › hypogonadism › gonadal dysgenesis › 46,XY complete gonadal dysgenesis › 46,XY disorder of sex development due to testicular 17,20-desmolase deficiency

Related subtypes (11): 46,XY sex reversal 4, 46,XY sex reversal 7, 46,XY sex reversal 2, 46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome, 46,XY sex reversal 3, 46,XY sex reversal 5, 46,XY sex reversal 6, 46,XY sex reversal 9, 46,XY sex reversal 10, 46,XY sex reversal 1, 46,XY sex reversal 11

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

11 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 4 pathogenic, 1 risk factor, 1 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
30064	NM_001393392.1(AKR1C2):c.235A>G (p.Ile79Val)	AKR1C2	Pathogenic	no assertion criteria provided
30065	NM_001393392.1(AKR1C2):c.270T>G (p.His90Gln)	AKR1C2	Pathogenic	no assertion criteria provided
30066	NM_001393392.1(AKR1C2):c.899A>C (p.Asn300Thr)	AKR1C2	Pathogenic	no assertion criteria provided
30067	NM_001393392.1(AKR1C2):c.666T>G (p.His222Gln)	AKR1C2	Pathogenic	no assertion criteria provided
30068	NM_001818.5(AKR1C4):c.85-106G>T	AKR1C4	risk factor	no assertion criteria provided
2690870	NM_001393392.1(AKR1C2):c.827_828del (p.Arg276fs)	AKR1C2	Uncertain significance	criteria provided, single submitter
3065936	NM_001393392.1(AKR1C2):c.158_159del (p.His53fs)	AKR1C2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3731486	NM_001393392.1(AKR1C2):c.487A>G (p.Ile163Val)	AKR1C2	Uncertain significance	criteria provided, single submitter
3393208	NM_001818.5(AKR1C4):c.220G>A (p.Val74Met)	AKR1C4	Uncertain significance	criteria provided, single submitter
434114	NM_001393392.1(AKR1C2):c.441A>G (p.Thr147=)	AKR1C2	Benign	criteria provided, multiple submitters, no conflicts
805966	NM_001393392.1(AKR1C2):c.666T>C (p.His222=)	AKR1C2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
AKR1C2	Supportive	Autosomal recessive	46,XY disorder of sex development due to testicular 17,20-desmolase deficiency	3
AKR1C4	Limited	Autosomal recessive	46,XY disorder of sex development due to testicular 17,20-desmolase deficiency	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AKR1C2	Orphanet:443087	46,XY difference of sex development due to testicular 17,20-desmolase deficiency
AKR1C4	Orphanet:443087	46,XY difference of sex development due to testicular 17,20-desmolase deficiency

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
AKR1C2	HGNC:385	ENSG00000151632	P52895	Aldo-keto reductase family 1 member C2	gencc,clinvar
AKR1C4	HGNC:387	ENSG00000198610	P17516	Aldo-keto reductase family 1 member C4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AKR1C2	Aldo-keto reductase family 1 member C2	Cytosolic aldo-keto reductase that catalyzes NADPH-dependent reduction of ketosteroids to hydroxysteroids.
AKR1C4	Aldo-keto reductase family 1 member C4	Cytosolic aldo-keto reductase that catalyzes NADPH-dependent reduction of ketosteroids to hydroxysteroids.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	2	12.0×	0.007

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AKR1C2	Enzyme (other)	yes	1.1.1.213	Aldo/ket_reductase_CS, AKR, NADP_OxRdtase_dom
AKR1C4	Enzyme (other)	yes	1.1.1.357	Aldo/ket_reductase_CS, AKR, NADP_OxRdtase_dom

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lobe of liver	2
islet of Langerhans	1
olfactory segment of nasal mucosa	1
gall bladder	1
liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AKR1C2	159	ubiquitous	marker	islet of Langerhans, right lobe of liver, olfactory segment of nasal mucosa
AKR1C4	74	tissue_specific	marker	right lobe of liver, liver, gall bladder

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AKR1C2	1,541
AKR1C4	1,180

Intra-cohort edges

A	B	Sources
AKR1C2	AKR1C4	biogrid_interaction, intact

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AKR1C2	P52895	16
AKR1C4	P17516	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Synthesis of bile acids and bile salts via 24-hydroxycholesterol	2	878.5×	1e-05	AKR1C2, AKR1C4
Synthesis of bile acids and bile salts via 27-hydroxycholesterol	2	761.3×	1e-05	AKR1C2, AKR1C4
Bile acid and bile salt metabolism	2	496.5×	1e-05	AKR1C2, AKR1C4
Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol	2	456.8×	1e-05	AKR1C2, AKR1C4
Synthesis of bile acids and bile salts	2	407.9×	2e-05	AKR1C2, AKR1C4
Metabolism of steroids	2	137.6×	1e-04	AKR1C2, AKR1C4
Metabolism of lipids	2	31.6×	0.002	AKR1C2, AKR1C4
Metabolism of fat-soluble vitamins	1	190.3×	0.009	AKR1C4
Visual phototransduction	1	129.8×	0.010	AKR1C4
Retinoid metabolism and transport	1	124.1×	0.010	AKR1C4
Metabolism	2	11.6×	0.010	AKR1C2, AKR1C4
Metabolism of vitamins and cofactors	1	58.3×	0.019	AKR1C4
Sensory Perception	1	47.6×	0.021	AKR1C4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cellular response to jasmonic acid stimulus	2	4213.0×	7e-07	AKR1C2, AKR1C4
progesterone metabolic process	2	1685.2×	2e-06	AKR1C2, AKR1C4
daunorubicin metabolic process	2	1532.0×	2e-06	AKR1C2, AKR1C4
doxorubicin metabolic process	2	1296.3×	2e-06	AKR1C2, AKR1C4
prostaglandin metabolic process	2	842.6×	4e-06	AKR1C2, AKR1C4
steroid metabolic process	2	337.0×	2e-05	AKR1C2, AKR1C4
cellular response to prostaglandin D stimulus	1	1203.7×	0.002	AKR1C2
androgen metabolic process	1	443.5×	0.005	AKR1C4
bile acid and bile salt transport	1	324.1×	0.005	AKR1C4
bile acid biosynthetic process	1	312.1×	0.005	AKR1C4
digestion	1	312.1×	0.005	AKR1C2
retinoid metabolic process	1	247.8×	0.005	AKR1C4
epithelial cell differentiation	1	87.8×	0.014	AKR1C2
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	39.2×	0.029	AKR1C2
G protein-coupled receptor signaling pathway	1	18.1×	0.058	AKR1C2
positive regulation of cell population proliferation	1	16.8×	0.059	AKR1C2

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
AKR1C2	DIAZEPAM
AKR1C4	FLURBIPROFEN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AKR1C2	11	4
AKR1C4	2	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DIAZEPAM	4	AKR1C2
NAPROXEN	4	AKR1C2
DEXIBUPROFEN	4	AKR1C2
BERBERINE	4	AKR1C2
MECLOFENAMIC ACID	4	AKR1C2
FLURBIPROFEN	4	AKR1C2, AKR1C4
INDOMETHACIN	4	AKR1C2, AKR1C4
MEFENAMIC ACID	4	AKR1C2
MEDROXYPROGESTERONE ACETATE	4	AKR1C2
FLUFENAMIC ACID	2	AKR1C2
FENAMIC ACID	1	AKR1C2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
AKR1C2	80	Binding:62, ADMET:18
AKR1C4	32	Binding:29, ADMET:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AKR1C2	1.1.1.213, 1.1.1.357, 1.1.1.50, 1.3.1.20	3alpha-hydroxysteroid 3-dehydrogenase (Re-specific), 3alpha-hydroxysteroid 3-dehydrogenase, 3alpha-hydroxysteroid 3-dehydrogenase (Si-specific), trans-1,2-dihydrobenzene-1,2-diol dehydrogenase
AKR1C4	1.1.1.357	3alpha-hydroxysteroid 3-dehydrogenase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

11 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
DIAZEPAM	4	AKR1C2
NAPROXEN	4	AKR1C2
DEXIBUPROFEN	4	AKR1C2
BERBERINE	4	AKR1C2
MECLOFENAMIC ACID	4	AKR1C2
FLURBIPROFEN	4	AKR1C2, AKR1C4
INDOMETHACIN	4	AKR1C2, AKR1C4
MEFENAMIC ACID	4	AKR1C2
MEDROXYPROGESTERONE ACETATE	4	AKR1C2
FLUFENAMIC ACID	2	AKR1C2
FENAMIC ACID	1	AKR1C2

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	AKR1C2, AKR1C4
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.