46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency

Summary

46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency (MONDO:0009923) is a disease caused by SRD5A2 (GenCC Strong), with 4 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: SRD5A2 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 302
• Phenotypes (HPO): 10

Clinical features

Signs & symptoms

Clinical features (HPO)

10 HPO clinical features (Orphanet curated; top 10 by frequency):

HPO ID	Term	Frequency
HP:0000028	Cryptorchidism	Very frequent (80-99%)
HP:0000033	Ambiguous genitalia, male	Very frequent (80-99%)
HP:0000046	Small scrotum	Very frequent (80-99%)
HP:0000048	Bifid scrotum	Very frequent (80-99%)
HP:0000051	Perineal hypospadias	Very frequent (80-99%)
HP:0000062	Ambiguous genitalia	Very frequent (80-99%)
HP:0000144	Decreased fertility	Very frequent (80-99%)
HP:0000818	Abnormality of the endocrine system	Very frequent (80-99%)
HP:0008736	Hypoplasia of penis	Very frequent (80-99%)
HP:0100779	Urogenital sinus anomaly	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency
Mondo ID	MONDO:0009923
MeSH	C535830
OMIM	264600
Orphanet	753
ICD-11	1028755501
NCIT	C98699
SNOMED CT	57514000
UMLS	C0268297
MedGen	75667
GARD	0005680
MedDRA	10000029
Is cancer (heuristic)	no

Also known as: 3-oxo-5 Alpha-steroid Delta 4-dehydrogenase deficiency · 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency · 46,XY DSD due to 5-alpha-reductase 2 deficiency · 5 Alpha steroid reductase 2 deficiency · 5-alpha reductase deficiency · Male pseudohermaphroditism due to 5-alpha-reductase 2 deficiency · PPSH · pseudovaginal perineoscrotal hypospadias · steroid 5-alpha-reductase deficiency

Data availability: 302 ClinVar variants · 3 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inherited lipid metabolism disorder › 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency

Related subtypes (28): cortisone reductase deficiency, familial hyperlipidemia, hypolipoproteinemia, steroid inherited metabolic disorder, corticosterone methyloxidase type 1 deficiency, lipoid proteinosis, vitamin D hydroxylation-deficient rickets, type 1B, mitochondrial trifunctional protein deficiency, pancreatic triacylglycerol lipase deficiency, glucocorticoid resistance, syndromic dyslipidemia, inborn disorder of glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation, disorder of plasmalogens biosynthesis, disorder of phospholipids, sphingolipids and fatty acids biosynthesis, inborn disorder of ketolysis, lysosomal lipid storage disorder, sterol metabolism disorder, disorder of sphingolipid biosynthesis, glycosylphosphatidylinositol biosynthesis defect 18, neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures, developmental and epileptic encephalopathy, 77, developmental and epileptic encephalopathy, 80, developmental and epileptic encephalopathy, 55, inherited fatty acid metabolism disorder, glycosylphosphatidylinositol biosynthesis defect 16, glycosylphosphatidylinositol biosynthesis defect 15, glycosylphosphatidylinositol biosynthesis defect 17, CYP7B1-related disorder of oxysterol accumulation

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

302 retrieved; paginated sample, class counts are floors:

107 likely benign, 71 pathogenic, 53 uncertain significance, 25 benign, 21 pathogenic/likely pathogenic, 14 conflicting classifications of pathogenicity, 9 likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1298362	NM_000348.4(SRD5A2):c.[169G>T;691C>T]		Pathogenic	criteria provided, single submitter
427837	NM_000348.3(SRD5A2):c.[548-9T>G];[680G>A]		Pathogenic	criteria provided, single submitter
427841	NM_000348.3(SRD5A2):c.[680G>A];[694C>G]		Pathogenic	criteria provided, single submitter
1298363	NM_000348.4(SRD5A2):c.169G>T (p.Glu57Ter)	SRD5A2	Pathogenic	criteria provided, single submitter
1298365	NM_000348.4(SRD5A2):c.589G>A (p.Glu197Lys)	SRD5A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1410942	NM_000348.4(SRD5A2):c.357del (p.Phe118_Cys119insTer)	SRD5A2	Pathogenic	criteria provided, single submitter
1454899	NC_000002.11:g.(?31751266)(31758856_?)del	SRD5A2	Pathogenic	criteria provided, single submitter
1457456	NC_000002.11:g.(?31751266)(31751352_?)del	SRD5A2	Pathogenic	criteria provided, single submitter
1802209	NM_000348.4(SRD5A2):c.10C>T (p.Gln4Ter)	SRD5A2	Pathogenic	criteria provided, single submitter
2444013	NM_000348.4(SRD5A2):c.383_384delinsGA (p.Tyr128Ter)	SRD5A2	Pathogenic	criteria provided, single submitter
2674673	NM_000348.4(SRD5A2):c.80_87del (p.Val27fs)	SRD5A2	Pathogenic	criteria provided, single submitter
2674674	NM_000348.4(SRD5A2):c.311G>A (p.Gly104Glu)	SRD5A2	Pathogenic	criteria provided, single submitter
2674675	NM_000348.4(SRD5A2):c.383A>G (p.Tyr128Cys)	SRD5A2	Pathogenic	criteria provided, multiple submitters, no conflicts
2674676	NM_000348.4(SRD5A2):c.574G>A (p.Ala192Thr)	SRD5A2	Pathogenic	criteria provided, single submitter
2674677	NM_000348.4(SRD5A2):c.587G>A (p.Gly196Asp)	SRD5A2	Pathogenic	criteria provided, single submitter
2674678	NM_000348.4(SRD5A2):c.699-1G>A	SRD5A2	Pathogenic	criteria provided, single submitter
2674680	NM_000348.4(SRD5A2):c.698+1G>T	SRD5A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2674681	NM_000348.4(SRD5A2):c.743C>A (p.Ala248Asp)	SRD5A2	Pathogenic	criteria provided, single submitter
2716510	NM_000348.4(SRD5A2):c.433C>T (p.Arg145Trp)	SRD5A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2734142	NM_000348.4(SRD5A2):c.689A>C (p.His230Pro)	SRD5A2	Pathogenic	criteria provided, single submitter
2734143	NM_000348.4(SRD5A2):c.418del (p.Trp140fs)	SRD5A2	Pathogenic	criteria provided, single submitter
2734145	NM_000348.4(SRD5A2):c.158G>A (p.Trp53Ter)	SRD5A2	Pathogenic	criteria provided, single submitter
2735335	NM_000348.4(SRD5A2):c.82_88del (p.Ala28fs)	SRD5A2	Pathogenic	criteria provided, single submitter
2756480	NM_000348.4(SRD5A2):c.564del (p.Thr187_Tyr188insTer)	SRD5A2	Pathogenic	criteria provided, single submitter
2762010	NM_000348.4(SRD5A2):c.687del (p.His230fs)	SRD5A2	Pathogenic	criteria provided, single submitter
2764310	NM_000348.4(SRD5A2):c.602G>A (p.Trp201Ter)	SRD5A2	Pathogenic	criteria provided, single submitter
2790633	NM_000348.4(SRD5A2):c.544C>T (p.Gln182Ter)	SRD5A2	Pathogenic	criteria provided, single submitter
2810971	NM_000348.4(SRD5A2):c.547+1G>C	SRD5A2	Pathogenic	criteria provided, single submitter
2858235	NM_000348.4(SRD5A2):c.144del (p.Ala49fs)	SRD5A2	Pathogenic	criteria provided, single submitter
2862678	NM_000348.4(SRD5A2):c.431dup (p.Arg145fs)	SRD5A2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 12 · 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
SRD5A2	Strong	Autosomal recessive	46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SRD5A2	Orphanet:1331	Familial prostate cancer
SRD5A2	Orphanet:753	46,XY difference of sex development due to 5-alpha-reductase 2 deficiency
SOX9	Orphanet:140	Campomelic dysplasia
SOX9	Orphanet:2138	46,XX ovotesticular difference of sex development
SOX9	Orphanet:242	46,XY complete gonadal dysgenesis
SOX9	Orphanet:251510	46,XY partial gonadal dysgenesis
SOX9	Orphanet:393	46,XX testicular difference of sex development
SOX9	Orphanet:718	Isolated Pierre Robin sequence
CHD7	Orphanet:138	CHARGE syndrome
CHD7	Orphanet:39041	Omenn syndrome
CHD7	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
CHD7	Orphanet:478	Kallmann syndrome

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SRD5A2	HGNC:11285	ENSG00000277893	P31213	3-oxo-5-alpha-steroid 4-dehydrogenase 2	gencc,clinvar
SOX9	HGNC:11204	ENSG00000125398	P48436	Transcription factor SOX-9	clinvar
CHD7	HGNC:20626	ENSG00000171316	Q9P2D1	ATP-dependent chromatin remodeler CHD7	clinvar
ZFPM2-AS1	HGNC:50698	ENSG00000251003		ZFPM2 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SRD5A2	3-oxo-5-alpha-steroid 4-dehydrogenase 2	Converts testosterone (T) into 5-alpha-dihydrotestosterone (DHT) and progesterone or corticosterone into their corresponding 5-alpha-3-oxosteroids.
SOX9	Transcription factor SOX-9	Transcription factor that plays a key role in chondrocytes differentiation and skeletal development.
CHD7	ATP-dependent chromatin remodeler CHD7	ATP-dependent chromatin-remodeling factor, slides nucleosomes along DNA; nucleosome sliding requires ATP.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.25

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)	1	3.0×	0.605
Transcription factor	1	2.1×	0.605
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SRD5A2	Enzyme (other)	yes	1.3.1.22	3-oxo-5_a-steroid_4-DH_C, 3-oxo-5-alpha-steroid_4-DH, SRD5A/TECR
SOX9	Transcription factor	no		HMG_box_dom, Sox_N, HMG_box_dom_sf
CHD7	Other/Unknown	no		SNF2_N, Chromo/chromo_shadow_dom, Helicase_C-like
ZFPM2-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bronchial epithelial cell	1
corpus epididymis	1
epithelium of bronchus	1
cranial nerve II	1
hair follicle	1
ventricular zone	1
cerebellar vermis	1
secondary oocyte	1
sural nerve	1
endometrium	1
male germ line stem cell (sensu Vertebrata) in testis	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SRD5A2	66	tissue_specific	marker	corpus epididymis, bronchial epithelial cell, epithelium of bronchus
SOX9	274	ubiquitous	marker	ventricular zone, cranial nerve II, hair follicle
CHD7	269	ubiquitous	marker	secondary oocyte, cerebellar vermis, sural nerve
ZFPM2-AS1	129	broad	marker	right uterine tube, endometrium, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SOX9	4,935
CHD7	4,819
SRD5A2	1,103
ZFPM2-AS1	0

Intra-cohort edges

A	B	Sources
CHD7	SOX9	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CHD7	Q9P2D1	3
SRD5A2	P31213	1
SOX9	P48436	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Androgen biosynthesis	1	346.1×	0.032	SRD5A2
Transcriptional regulation of testis differentiation	1	237.9×	0.032	SOX9
Developmental Lineage of Multipotent Pancreatic Progenitor Cells	1	200.3×	0.032	SOX9
Metabolism of steroid hormones	1	173.0×	0.032	SRD5A2
Developmental Lineage of Pancreatic Acinar Cells	1	100.2×	0.033	SOX9
Transcriptional regulation by RUNX2	1	84.6×	0.033	SOX9
Deactivation of the beta-catenin transactivating complex	1	77.7×	0.033	SOX9
Developmental Lineage of Pancreatic Ductal Cells	1	76.1×	0.033	SOX9
Developmental Cell Lineages	1	74.6×	0.033	SOX9
Transcriptional and post-translational regulation of MITF-M expression and activity	1	59.5×	0.037	SOX9
CHD6, CHD7, CHD8, CHD9 subfamily	1	49.4×	0.039	CHD7
Metabolism of steroids	1	45.9×	0.039	SRD5A2
TCF dependent signaling in response to WNT	1	39.2×	0.039	SOX9
MITF-M-regulated melanocyte development	1	38.1×	0.039	SOX9
Signaling by WNT	1	37.3×	0.039	SOX9
Metabolism of lipids	1	10.5×	0.127	SRD5A2
RNA Polymerase II Transcription	1	7.5×	0.165	SOX9
Gene expression (Transcription)	1	6.0×	0.194	SOX9
Generic Transcription Pathway	1	5.0×	0.213	SOX9
Developmental Biology	1	4.8×	0.213	SOX9
Metabolism	1	3.9×	0.248	SRD5A2
Signal Transduction	1	3.4×	0.267	SOX9

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
female genitalia development	2	1605.0×	8e-05	SRD5A2, CHD7
right ventricular compact myocardium morphogenesis	1	5617.3×	0.004	CHD7
phthalate metabolic process	1	5617.3×	0.004	SRD5A2
negative regulation of immune system process	1	2808.7×	0.004	SOX9
biphenyl metabolic process	1	2808.7×	0.004	SRD5A2
dibenzo-p-dioxin metabolic process	1	2808.7×	0.004	SRD5A2
epithelial cell proliferation involved in prostatic bud elongation	1	2808.7×	0.004	SOX9
regulation of cell proliferation involved in tissue homeostasis	1	2808.7×	0.004	SOX9
regulation of branching involved in lung morphogenesis	1	2808.7×	0.004	SOX9
cell proliferation involved in heart morphogenesis	1	2808.7×	0.004	SOX9
regulation of epithelial cell proliferation involved in lung morphogenesis	1	2808.7×	0.004	SOX9
heart valve formation	1	1872.4×	0.004	SOX9
neural crest cell fate specification	1	1872.4×	0.004	SOX9
male germ-line sex determination	1	1872.4×	0.004	SOX9
cranial nerve development	1	1872.4×	0.004	CHD7
olfactory nerve development	1	1872.4×	0.004	CHD7
intrahepatic bile duct development	1	1872.4×	0.004	SOX9
regulation of growth hormone secretion	1	1872.4×	0.004	CHD7
bronchus cartilage development	1	1872.4×	0.004	SOX9
lung smooth muscle development	1	1872.4×	0.004	SOX9
ureter urothelium development	1	1872.4×	0.004	SOX9
ureter smooth muscle cell differentiation	1	1872.4×	0.004	SOX9
response to biphenyl	1	1872.4×	0.004	SRD5A2
negative regulation of beta-catenin-TCF complex assembly	1	1872.4×	0.004	SOX9
retina development in camera-type eye	2	170.2×	0.004	SOX9, CHD7
male gonad development	2	104.0×	0.004	SRD5A2, SOX9
skeletal system development	2	83.8×	0.004	SOX9, CHD7
chromatin remodeling	2	48.6×	0.004	SOX9, CHD7
transcription by RNA polymerase II	2	47.0×	0.004	SOX9, CHD7
glial cell fate specification	1	1404.3×	0.004	SOX9

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) 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
SRD5A2	FINASTERIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SRD5A2	5	4
SOX9	0	0
CHD7	0	0
ZFPM2-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FINASTERIDE	4	SRD5A2
GAMOLENIC ACID	3	SRD5A2
EPRISTERIDE	2	SRD5A2
TUROSTERIDE	2	SRD5A2
BEXLOSTERIDE	2	SRD5A2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
SRD5A2	119	Binding:115, Functional:4
SOX9	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SRD5A2	1.3.1.22, 1.3.99.5	3-oxo-5alpha-steroid 4-dehydrogenase (NADP+), 3-oxo-5alpha-steroid 4-dehydrogenase (acceptor)

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
SRD5A2	119

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

5 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)
FINASTERIDE	4	SRD5A2
GAMOLENIC ACID	3	SRD5A2
EPRISTERIDE	2	SRD5A2
TUROSTERIDE	2	SRD5A2
BEXLOSTERIDE	2	SRD5A2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SRD5A2
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	3	SOX9, CHD7, ZFPM2-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SOX9	3	—
CHD7	0	—
ZFPM2-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.