hypospadias 1, X-linked

Summary

hypospadias 1, X-linked (MONDO:0010384) is a disease with 3 cohort genes.

At a glance

• Cohort genes: 3
• ClinVar variants: 22

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypospadias 1, X-linked
Mondo ID	MONDO:0010384
MeSH	C567482
OMIM	300633
UMLS	C2678098
MedGen	394735
GARD	0018185
Is cancer (heuristic)	no

Also known as: hypospadias 1, X-linked · hypospadias 1, X-linked, X-linked recessive · HYSP1

Data availability: 22 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hypospadias › hypospadias 1, X-linked

Related subtypes (4): hypospadias 3, autosomal, hypospadias 2, X-linked, hypospadias 4, X-linked, isolated female hypospadias

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

22 retrieved; paginated sample, class counts are floors:

4 conflicting classifications of pathogenicity, 4 pathogenic, 4 uncertain significance, 4 benign/likely benign, 2 likely benign, 2 pathogenic/likely pathogenic, 1 likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2572770	NM_000044.6(AR):c.2270A>G (p.Asn757Ser)	AR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3382976	NM_000044.6(AR):c.154_220del (p.Ala52fs)	AR	Pathogenic	criteria provided, single submitter
3598420	NM_000044.6(AR):c.610G>T (p.Glu204Ter)	AR	Pathogenic	criteria provided, single submitter
492801	NM_000044.6(AR):c.2612C>T (p.Ala871Val)	AR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9806	NM_000044.6(AR):c.2599G>A (p.Val867Met)	AR	Pathogenic	criteria provided, multiple submitters, no conflicts
9824	NM_000044.6(AR):c.2610T>G (p.Ile870Met)	AR	Pathogenic	no assertion criteria provided
2413120	NM_000198.4(HSD3B2):c.507T>A (p.Asn169Lys)	HSD3B2	Likely pathogenic	no assertion criteria provided
1488550	NM_000044.6(AR):c.7G>A (p.Val3Met)	AR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
216890	NM_000044.6(AR):c.1174C>T (p.Pro392Ser)	AR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
402390	NM_000044.6(AR):c.173A>T (p.Gln58Leu)	AR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
804019	NM_000044.6(AR):c.1424C>T (p.Ala475Val)	AR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
417975	NM_000044.6(AR):c.171GCA[36] (p.Gln68_Gln80dup)	AR	Uncertain significance	criteria provided, single submitter
492780	NM_000044.6(AR):c.1153G>T (p.Ala385Ser)	AR	Uncertain significance	criteria provided, single submitter
587547	NM_000044.6(AR):c.1370GCG[5] (p.Gly462_Gly473del)	AR	Uncertain significance	criteria provided, multiple submitters, no conflicts
9840	NM_000044.6(AR):c.1645C>T (p.Pro549Ser)	AR	Uncertain significance	criteria provided, single submitter
1189467	NM_000044.6(AR):c.171GCA[35] (p.Gln69_Gln80dup)	AR	Likely benign	criteria provided, multiple submitters, no conflicts
422605	NM_000044.6(AR):c.171GCA[32] (p.Gln72_Gln80dup)	AR	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
434254	NM_000044.6(AR):c.171GCA[18] (p.Gln76_Gln80del)	AR	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
434265	NM_000044.6(AR):c.1370GCG[19] (p.Gly472_Gly473dup)	AR	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
516217	NM_000044.6(AR):c.171GCA[14] (p.Gln72_Gln80del)	AR	Likely benign	criteria provided, multiple submitters, no conflicts
804018	NM_000044.6(AR):c.528C>A (p.Ser176Arg)	AR	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
464798	NM_000044.6(AR):c.171GCA[22] (p.Gln80del)	LOC109504725	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HSD3B2	Orphanet:90791	Congenital adrenal hyperplasia due to 3-beta-hydroxysteroid dehydrogenase deficiency
AR	Orphanet:481	Kennedy disease
AR	Orphanet:90797	Partial androgen insensitivity syndrome
AR	Orphanet:95706	Non-syndromic posterior hypospadias
AR	Orphanet:99429	Complete androgen insensitivity syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HSD3B2	HGNC:5218	ENSG00000203859	P26439	3 beta-hydroxysteroid dehydrogenase/Delta 5–>4-isomerase type 2	clinvar
AR	HGNC:644	ENSG00000169083	P10275	Androgen receptor	clinvar
AREG	HGNC:651	ENSG00000109321	P15514	Amphiregulin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HSD3B2	3 beta-hydroxysteroid dehydrogenase/Delta 5–>4-isomerase type 2	3-beta-HSD is a bifunctional enzyme, that catalyzes the oxidative conversion of Delta(5)-ene-3-beta-hydroxy steroid, and the oxidative conversion of ketosteroids.
AR	Androgen receptor	Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues.
AREG	Amphiregulin	Ligand of the EGF receptor/EGFR.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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
Nuclear receptor	1	128.6×	0.023
Enzyme (other)	1	4.0×	0.345
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HSD3B2	Enzyme (other)	yes	1.1.1.145	3Beta_OHSteriod_DH/Estase, NAD(P)-bd_dom_sf, Lipid_A_modif_metabolic_enz
AR	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Andrgn_rcpt, Znf_hrmn_rcpt
AREG	Other/Unknown	no		EGF

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal cortex	1
right adrenal gland	1
right adrenal gland cortex	1
nipple	1
seminal vesicle	1
urethra	1
endometrium epithelium	1
mucosa of urinary bladder	1
right lung	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HSD3B2	157	tissue_specific	yes	right adrenal gland, right adrenal gland cortex, adrenal cortex
AR	250	ubiquitous	marker	seminal vesicle, urethra, nipple
AREG	216	ubiquitous	marker	mucosa of urinary bladder, endometrium epithelium, right lung

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AR	7,400
HSD3B2	2,968
AREG	2,745

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AR	P10275	95
AREG	P15514	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HSD3B2	P26439	94.30

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 70. Enrichment computed across 3 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
Signaling by Overexpressed Wild-Type EGFR in Cancer	1	951.7×	0.023	AREG
Mineralocorticoid biosynthesis	1	475.8×	0.023	HSD3B2
Inhibition of Signaling by Overexpressed EGFR	1	423.0×	0.023	AREG
Signaling by EGFR in Cancer	1	380.7×	0.023	AREG
EGFR interacts with phospholipase C-gamma	1	380.7×	0.023	AREG
Androgen biosynthesis	1	346.1×	0.023	HSD3B2
NFE2L2 regulating tumorigenic genes	1	317.2×	0.023	AREG
Glucocorticoid biosynthesis	1	292.8×	0.023	HSD3B2
RUNX2 regulates bone development	1	271.9×	0.023	AR
GRB2 events in EGFR signaling	1	253.8×	0.023	AREG
SHC1 events in EGFR signaling	1	237.9×	0.023	AREG
Cellular responses to stress	2	24.6×	0.023	AR, AREG
Cellular responses to stimuli	2	21.0×	0.023	AR, AREG
GAB1 signalosome	1	211.5×	0.024	AREG
Developmental Lineage of Mammary Gland Myoepithelial Cells	1	181.3×	0.024	AREG
Metabolism of steroid hormones	1	173.0×	0.024	HSD3B2
RUNX2 regulates osteoblast differentiation	1	152.3×	0.024	AR
Developmental Lineage of Mammary Gland Luminal Epithelial Cells	1	152.3×	0.024	AREG
Estrogen-dependent nuclear events downstream of ESR-membrane signaling	1	146.4×	0.024	AREG
PI3K/AKT Signaling in Cancer	1	122.8×	0.024	AREG
EGFR downregulation	1	115.3×	0.024	AREG
SUMOylation of intracellular receptors	1	112.0×	0.024	AR
Cargo concentration in the ER	1	112.0×	0.024	AREG
Nuclear events mediated by NFE2L2	1	112.0×	0.024	AREG
Signaling by EGFR	1	108.8×	0.024	AREG
RHO GTPases activate PKNs	1	105.7×	0.024	AR
Post-translational protein modification	2	12.8×	0.024	AR, AREG
Negative regulation of the PI3K/AKT network	1	92.8×	0.027	AREG
Transcriptional regulation by RUNX2	1	84.6×	0.028	AR
Nuclear Receptor transcription pathway	1	66.8×	0.035	AR

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
mammary gland alveolus development	2	660.9×	2e-04	AR, AREG
male somatic sex determination	1	5617.3×	0.004	AR
prostate induction	1	5617.3×	0.004	AR
regulation of developmental growth	1	2808.7×	0.004	AR
lateral sprouting involved in mammary gland duct morphogenesis	1	2808.7×	0.004	AR
positive regulation of integrin biosynthetic process	1	1872.4×	0.004	AR
dichotomous subdivision of terminal units involved in mammary gland duct morphogenesis	1	1872.4×	0.004	AREG
tertiary branching involved in mammary gland duct morphogenesis	1	1872.4×	0.004	AR
positive regulation of epithelial cell proliferation involved in prostate gland development	1	1872.4×	0.004	AR
morphogenesis of an epithelial fold	1	1404.3×	0.004	AR
C21-steroid hormone metabolic process	1	1123.5×	0.004	HSD3B2
animal organ formation	1	1123.5×	0.004	AR
male genitalia morphogenesis	1	1123.5×	0.004	AR
epithelial cell differentiation involved in prostate gland development	1	1123.5×	0.004	AR
cell-cell signaling	2	46.4×	0.004	AR, AREG
mammary gland branching involved in thelarche	1	936.2×	0.004	AREG
epithelial cell proliferation involved in mammary gland duct elongation	1	936.2×	0.004	AREG
cellular response to testosterone stimulus	1	802.5×	0.005	AR
prostate gland growth	1	702.2×	0.005	AR
androgen biosynthetic process	1	624.1×	0.005	HSD3B2
prostate gland epithelium morphogenesis	1	624.1×	0.005	AR
ERBB2-EGFR signaling pathway	1	561.7×	0.006	AREG
positive regulation of intracellular estrogen receptor signaling pathway	1	401.2×	0.007	AR
Leydig cell differentiation	1	401.2×	0.007	AR
positive regulation of insulin-like growth factor receptor signaling pathway	1	401.2×	0.007	AR
membraneless organelle assembly	1	374.5×	0.007	AR
regulation of systemic arterial blood pressure	1	351.1×	0.007	AR
cellular response to steroid hormone stimulus	1	351.1×	0.007	AR
positive regulation of keratinocyte proliferation	1	330.4×	0.007	AREG
intracellular receptor signaling pathway	1	330.4×	0.007	AR

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 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
AR	PROGESTERONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AR	116	4
HSD3B2	0	0
AREG	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PROGESTERONE	4	AR
ENZALUTAMIDE	4	AR
HYDROCORTISONE ACETATE	4	AR
EPLERENONE	4	AR
CHLORMADINONE ACETATE	4	AR
ARIPIPRAZOLE	4	AR
MOMETASONE FUROATE	4	AR
TESTOSTERONE PROPIONATE	4	AR
ESTRADIOL ACETATE	4	AR
OXANDROLONE	4	AR
BECLOMETHASONE DIPROPIONATE	4	AR
DIFLORASONE DIACETATE	4	AR
ETHYNODIOL DIACETATE	4	AR
HALCINONIDE	4	AR
DYDROGESTERONE	4	AR
FLUMETHASONE PIVALATE	4	AR
HALOBETASOL PROPIONATE	4	AR
ESTRADIOL CYPIONATE	4	AR
CLOCORTOLONE PIVALATE	4	AR
FLURANDRENOLIDE	4	AR
MEGESTROL ACETATE	4	AR
NORETHINDRONE ACETATE	4	AR
SERTACONAZOLE	4	AR
PYRVINIUM	4	AR
PRASUGREL	4	AR
OXICONAZOLE	4	AR
NILUTAMIDE	4	AR
MIFEPRISTONE	4	AR
PREDNISOLONE	4	AR
ESTRADIOL	4	AR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
AR	2,100	Binding:1727, Functional:339, ADMET:33, Unclassified:1
HSD3B2	3	Binding:3
AREG	1	Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HSD3B2	1.1.1.145, 5.3.3.1	3beta-hydroxy-DELTA5-steroid dehydrogenase, steroid DELTA-isomerase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
AR	2,100

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

30 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)
PROGESTERONE	4	AR
ENZALUTAMIDE	4	AR
HYDROCORTISONE ACETATE	4	AR
EPLERENONE	4	AR
CHLORMADINONE ACETATE	4	AR
ARIPIPRAZOLE	4	AR
MOMETASONE FUROATE	4	AR
TESTOSTERONE PROPIONATE	4	AR
ESTRADIOL ACETATE	4	AR
OXANDROLONE	4	AR
BECLOMETHASONE DIPROPIONATE	4	AR
DIFLORASONE DIACETATE	4	AR
ETHYNODIOL DIACETATE	4	AR
HALCINONIDE	4	AR
DYDROGESTERONE	4	AR
FLUMETHASONE PIVALATE	4	AR
HALOBETASOL PROPIONATE	4	AR
ESTRADIOL CYPIONATE	4	AR
CLOCORTOLONE PIVALATE	4	AR
FLURANDRENOLIDE	4	AR
MEGESTROL ACETATE	4	AR
NORETHINDRONE ACETATE	4	AR
SERTACONAZOLE	4	AR
PYRVINIUM	4	AR
PRASUGREL	4	AR
OXICONAZOLE	4	AR
NILUTAMIDE	4	AR
MIFEPRISTONE	4	AR
PREDNISOLONE	4	AR
ESTRADIOL	4	AR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	AR
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	HSD3B2
E	Difficult family or no structure, no drug	1	AREG

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HSD3B2	3	—
AREG	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.