46,XY partial gonadal dysgenesis
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Also known as 46,XY partial testicular dysgenesis46,XY PGD
Summary
46,XY partial gonadal dysgenesis (MONDO:0016674) is a disease (an umbrella term covering 7 Mondo subtypes) with 11 cohort genes. The dominant Reactome pathway is Transcriptional regulation of testis differentiation (5 cohort genes).
At a glance
- Prevalence: Unknown (Worldwide)
- Umbrella term: 7 Mondo subtypes
- Cohort genes: 11
- ClinVar variants: 4
- Phenotypes (HPO): 43
Clinical features
Signs & symptoms
Clinical features (HPO)
43 HPO clinical features (Orphanet curated; top 43 by frequency):
| HPO ID | Term | Frequency |
|---|---|---|
| HP:0003251 | Male infertility | Very frequent (80-99%) |
| HP:0008214 | Decreased serum estradiol | Very frequent (80-99%) |
| HP:0008232 | Elevated circulating follicle stimulating hormone level | Very frequent (80-99%) |
| HP:0008665 | Clitoral hypertrophy | Very frequent (80-99%) |
| HP:0008726 | Hypoplasia of the vagina | Very frequent (80-99%) |
| HP:0008730 | Female external genitalia in individual with 46,XY karyotype | Very frequent (80-99%) |
| HP:0008734 | Decreased testicular size | Very frequent (80-99%) |
| HP:0008736 | Hypoplasia of penis | Very frequent (80-99%) |
| HP:0010464 | Streak ovary | Very frequent (80-99%) |
| HP:0011969 | Elevated circulating luteinizing hormone level | Very frequent (80-99%) |
| HP:0012244 | Abnormal sex determination | Very frequent (80-99%) |
| HP:0012870 | Vanishing testis | Very frequent (80-99%) |
| HP:0040171 | Decreased serum testosterone concentration | Very frequent (80-99%) |
| HP:0100779 | Urogenital sinus anomaly | Very frequent (80-99%) |
| HP:0000027 | Azoospermia | Very frequent (80-99%) |
| HP:0000045 | Abnormality of the scrotum | Very frequent (80-99%) |
| HP:0000047 | Hypospadias | Very frequent (80-99%) |
| HP:0000054 | Micropenis | Very frequent (80-99%) |
| HP:0000058 | Abnormality of the labia | Very frequent (80-99%) |
| HP:0000062 | Ambiguous genitalia | Very frequent (80-99%) |
| HP:0000133 | Gonadal dysgenesis | Very frequent (80-99%) |
| HP:0000142 | Abnormality of the vagina | Very frequent (80-99%) |
| HP:0000771 | Gynecomastia | Very frequent (80-99%) |
| HP:0000786 | Primary amenorrhea | Very frequent (80-99%) |
| HP:0000812 | Abnormal internal genitalia | Very frequent (80-99%) |
| HP:0000815 | Hypergonadotropic hypogonadism | Very frequent (80-99%) |
| HP:0000837 | Increased circulating gonadotropin level | Very frequent (80-99%) |
| HP:0000868 | Decreased fertility in females | Very frequent (80-99%) |
| HP:0000939 | Osteoporosis | Very frequent (80-99%) |
| HP:0002215 | Sparse axillary hair | Very frequent (80-99%) |
| HP:0002225 | Sparse pubic hair | Very frequent (80-99%) |
| HP:0000028 | Cryptorchidism | Frequent (30-79%) |
| HP:0000150 | Gonadoblastoma | Frequent (30-79%) |
| HP:0000823 | Delayed puberty | Frequent (30-79%) |
| HP:0000030 | Testicular gonadoblastoma | Occasional (5-29%) |
| HP:0000149 | Ovarian gonadoblastoma | Occasional (5-29%) |
| HP:0000846 | Adrenal insufficiency | Occasional (5-29%) |
| HP:0002750 | Delayed skeletal maturation | Occasional (5-29%) |
| HP:0008187 | Absence of secondary sex characteristics | Occasional (5-29%) |
| HP:0008193 | Primary gonadal insufficiency | Occasional (5-29%) |
| HP:0000100 | Nephrotic syndrome | Very rare (<1-4%) |
| HP:0002667 | Nephroblastoma | Very rare (<1-4%) |
| HP:0030680 | Abnormal cardiovascular system morphology | Very rare (<1-4%) |
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | 46,XY partial gonadal dysgenesis |
| Mondo ID | MONDO:0016674 |
| Orphanet | 251510 |
| SNOMED CT | 725045004 |
| UMLS | C4510744 |
| MedGen | 1388250 |
| GARD | 0017211 |
| Is cancer (heuristic) | no |
Also known as: 46,XY partial testicular dysgenesis · 46,XY PGD
Data availability: 4 ClinVar variants · 8 GenCC gene-disease records.
Disease family
An umbrella term covering 7 Mondo subtypes.
Classification path: disease › human disease › disease by body system or component › reproductive system disorder › gonadal disorder › disorder of sexual differentiation › 46 XY differences of sex development › 46,XY partial gonadal dysgenesis
Related subtypes (23): Frasier syndrome, WAGR syndrome, Denys-Drash syndrome, familial adrenal hypoplasia with absent pituitary luteinizing hormone, PAGOD syndrome, XY type gonadal dysgenesis-associated anomalies syndrome, 46,XY disorder of sex development due to 17-beta-hydroxysteroid dehydrogenase 3 deficiency, 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency, X-linked myotubular myopathy-abnormal genitalia syndrome, alpha thalassemia-X-linked intellectual disability syndrome, chondrodysplasia-pseudohermaphroditism syndrome, disorder of sex development-intellectual disability syndrome, 46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome, sudden infant death-dysgenesis of the testes syndrome, Meacham syndrome, Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency, distal monosomy 9p, dysmorphism-short stature-deafness-disorder of sex development syndrome, testicular agenesis, 46,XY ovotesticular disorder of sex development, penile agenesis, androgen insensitivity syndrome, male pseudohermaphroditism due to defective lh molecule
Subtypes (7): 46,XY sex reversal 4, 46,XY sex reversal 2, 46,XY sex reversal 3, 46,XY sex reversal 6, testicular anomalies with or without congenital heart disease, 46,XY sex reversal 9, 46,XY sex reversal 10
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
4 retrieved; paginated sample, class counts are floors:
1 pathogenic, 1 likely pathogenic, 1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 1691445 | NM_004959.5(NR5A1):c.991-1G>C | NR5A1 | Pathogenic | criteria provided, single submitter |
| 8098 | NM_006261.5(PROP1):c.301_302del (p.Leu102fs) | PROP1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 1691446 | NM_005633.4(SOS1):c.406T>C (p.Tyr136His) | SOS1 | Likely pathogenic | criteria provided, single submitter |
| 803030 | NM_021728.4(OTX2):c.425C>G (p.Pro142Arg) | OTX2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 83 · Orphanet: 49 · 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 |
|---|---|---|---|---|
| DHX37 | Supportive | Autosomal dominant | 46,XY complete gonadal dysgenesis | 9 |
| GATA4 | Supportive | Autosomal dominant | 46,XY partial gonadal dysgenesis | 15 |
| MAP3K1 | Supportive | Autosomal dominant | 46,XY complete gonadal dysgenesis | 7 |
| NR5A1 | Supportive | Autosomal dominant | 46,XY complete gonadal dysgenesis | 12 |
| SOX9 | Supportive | Autosomal dominant | 46,XY complete gonadal dysgenesis | 13 |
| SRY | Supportive | Autosomal dominant | 46,XY complete gonadal dysgenesis | 8 |
| WWOX | Supportive | Autosomal dominant | 46,XY partial gonadal dysgenesis | 11 |
| ZFPM2 | Supportive | Autosomal dominant | 46,XY partial gonadal dysgenesis | 8 |
Orphanet rare-disease linkage (cohort genes)
| Gene | Orphanet ID | Rare disease |
|---|---|---|
| NR5A1 | Orphanet:2138 | 46,XX ovotesticular difference of sex development |
| NR5A1 | Orphanet:242 | 46,XY complete gonadal dysgenesis |
| NR5A1 | Orphanet:243 | 46,XX gonadal dysgenesis |
| NR5A1 | Orphanet:251510 | 46,XY partial gonadal dysgenesis |
| NR5A1 | Orphanet:393 | 46,XX testicular difference of sex development |
| NR5A1 | Orphanet:399805 | Male infertility with azoospermia or oligozoospermia due to single gene mutation |
| 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 |
| SRY | Orphanet:1772 | 45,X/46,XY mixed gonadal dysgenesis |
| SRY | Orphanet:2138 | 46,XX ovotesticular difference of sex development |
| SRY | Orphanet:242 | 46,XY complete gonadal dysgenesis |
| SRY | Orphanet:251510 | 46,XY partial gonadal dysgenesis |
| SRY | Orphanet:393 | 46,XX testicular difference of sex development |
| WWOX | Orphanet:251510 | 46,XY partial gonadal dysgenesis |
| WWOX | Orphanet:284282 | Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to WWOX deficiency |
| WWOX | Orphanet:708171 | Facial dysmorphism-corpus callosum hypoplasia-infantile epileptic encephalopathy |
| WWOX | Orphanet:99977 | Squamous cell carcinoma of the esophagus |
| ZFPM2 | Orphanet:2140 | Congenital diaphragmatic hernia |
| ZFPM2 | Orphanet:251510 | 46,XY partial gonadal dysgenesis |
| ZFPM2 | Orphanet:3303 | Tetralogy of Fallot |
| DHX37 | Orphanet:242 | 46,XY complete gonadal dysgenesis |
| DHX37 | Orphanet:251510 | 46,XY partial gonadal dysgenesis |
| DHX37 | Orphanet:983 | Testicular regression syndrome |
| GATA4 | Orphanet:251071 | 8p23.1 microdeletion syndrome |
| GATA4 | Orphanet:251510 | 46,XY partial gonadal dysgenesis |
| GATA4 | Orphanet:3303 | Tetralogy of Fallot |
| GATA4 | Orphanet:334 | Hereditary atrial fibrillation |
| GATA4 | Orphanet:576232 | Partial atrioventricular septal defect with ventricular hypoplasia |
| GATA4 | Orphanet:99067 | Complete atrioventricular septal defect with ventricular hypoplasia |
| GATA4 | Orphanet:99068 | Complete atrioventricular septal defect-tetralogy of Fallot |
| GATA4 | Orphanet:99103 | Atrial septal defect, ostium secundum type |
| MAP3K1 | Orphanet:242 | 46,XY complete gonadal dysgenesis |
| MAP3K1 | Orphanet:251510 | 46,XY partial gonadal dysgenesis |
| SOS1 | Orphanet:2024 | Hereditary gingival fibromatosis |
| SOS1 | Orphanet:648 | Noonan syndrome |
| OTX2 | Orphanet:178364 | Syndromic microphthalmia type 5 |
| OTX2 | Orphanet:3157 | Septo-optic dysplasia spectrum |
| OTX2 | Orphanet:35612 | Nanophthalmos |
| OTX2 | Orphanet:95494 | Combined pituitary hormone deficiencies, genetic forms |
| OTX2 | Orphanet:98938 | Colobomatous microphthalmia |
| OTX2 | Orphanet:990 | Agnathia-holoprosencephaly-situs inversus syndrome |
| OTX2 | Orphanet:99001 | Butterfly-shaped pigment dystrophy |
| PROP1 | Orphanet:226307 | Hypothyroidism due to deficient transcription factors involved in pituitary development or function |
| PROP1 | Orphanet:90695 | Non-acquired panhypopituitarism |
| PROP1 | Orphanet:95494 | Combined pituitary hormone deficiencies, genetic forms |
Cohort genes → proteins
11 cohort genes, 11 distinct canonical proteins.
Evidence partition
| Subset | Genes |
|---|---|
| multi_evidence | 11 |
Cohort genes (full)
| Symbol | HGNC | Ensembl | UniProt | Name | Evidence |
|---|---|---|---|---|---|
| NR5A1 | HGNC:7983 | ENSG00000136931 | Q13285 | Steroidogenic factor 1 | gencc,clinvar |
| SOX9 | HGNC:11204 | ENSG00000125398 | P48436 | Transcription factor SOX-9 | gencc |
| SRY | HGNC:11311 | ENSG00000184895 | Q05066 | Sex-determining region Y protein | gencc |
| WWOX | HGNC:12799 | ENSG00000186153 | Q9NZC7 | WW domain-containing oxidoreductase | gencc |
| ZFPM2 | HGNC:16700 | ENSG00000169946 | Q8WW38 | Zinc finger protein ZFPM2 | gencc |
| DHX37 | HGNC:17210 | ENSG00000150990 | Q8IY37 | Probable ATP-dependent RNA helicase DHX37 | gencc |
| GATA4 | HGNC:4173 | ENSG00000136574 | P43694 | Transcription factor GATA-4 | gencc |
| MAP3K1 | HGNC:6848 | ENSG00000095015 | Q13233 | Mitogen-activated protein kinase kinase kinase 1 | gencc |
| SOS1 | HGNC:11187 | ENSG00000115904 | Q07889 | Son of sevenless homolog 1 | clinvar |
| OTX2 | HGNC:8522 | ENSG00000165588 | P32243 | Homeobox protein OTX2 | clinvar |
| PROP1 | HGNC:9455 | ENSG00000175325 | O75360 | Homeobox protein prophet of Pit-1 | clinvar |
Cohort function summary
Lead sentence per gene, UniProt-curated.
| Symbol | Protein name | Function (lead sentence) |
|---|---|---|
| NR5A1 | Steroidogenic factor 1 | Transcriptional activator. |
| SOX9 | Transcription factor SOX-9 | Transcription factor that plays a key role in chondrocytes differentiation and skeletal development. |
| SRY | Sex-determining region Y protein | Transcriptional regulator that controls a genetic switch in male development. |
| WWOX | WW domain-containing oxidoreductase | Putative oxidoreductase. |
| ZFPM2 | Zinc finger protein ZFPM2 | Transcription regulator that plays a central role in heart morphogenesis and development of coronary vessels from epicardium, by regulating genes that are essential during cardiogenesis. |
| DHX37 | Probable ATP-dependent RNA helicase DHX37 | ATP-binding RNA helicase that plays a role in maturation of the small ribosomal subunit in ribosome biogenesis. |
| GATA4 | Transcription factor GATA-4 | Transcriptional activator that binds to the consensus sequence 5’-AGATAG-3’ and plays a key role in cardiac development and function. |
| MAP3K1 | Mitogen-activated protein kinase kinase kinase 1 | Component of a protein kinase signal transduction cascade. |
| SOS1 | Son of sevenless homolog 1 | Promotes the exchange of Ras-bound GDP by GTP. |
| OTX2 | Homeobox protein OTX2 | Transcription factor probably involved in the development of the brain and the sense organs. |
| PROP1 | Homeobox protein prophet of Pit-1 | Possibly involved in the ontogenesis of pituitary gonadotropes, as well as somatotropes, lactotropes and caudomedial thyrotropes. |
Protein-family classification
Druggable: 2 · Difficult: 8 · Unknown: 1 · Druggable fraction: 0.18
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 |
|---|---|---|---|
| Transcription factor | 6 | 4.5× | 0.004 |
| Nuclear receptor | 1 | 35.1× | 0.070 |
| Scaffold/PPI | 2 | 3.1× | 0.217 |
| Kinase | 1 | 2.5× | 0.416 |
| Other/Unknown | 1 | 0.2× | 1.000 |
Per-gene assignment
| Symbol | Family | Druggable? | EC | InterPro (top 3) |
|---|---|---|---|---|
| NR5A1 | Nuclear receptor | yes | Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt | |
| SOX9 | Transcription factor | no | HMG_box_dom, Sox_N, HMG_box_dom_sf | |
| SRY | Transcription factor | no | HMG_box_dom, SRY, HMG_box_dom_sf | |
| WWOX | Scaffold/PPI | no | WW_dom, SDR_fam, WW_dom_sf | |
| ZFPM2 | Transcription factor | no | Znf_C2H2_type, Znf_CCHC_FOG, Znf_C2H2_sf | |
| DHX37 | Other/Unknown | no | Helicase_C-like, Helicase-assoc_dom, DEAD/DEAH_box_helicase_dom | |
| GATA4 | Transcription factor | no | Znf_GATA, GATA_N, Znf_NHR/GATA | |
| MAP3K1 | Kinase | yes | 2.7.11.25 | Prot_kinase_dom, Znf_RING, Znf_SWIM |
| SOS1 | Scaffold/PPI | no | DH_dom, Ras-like_Gua-exchang_fac_N, PH_domain | |
| OTX2 | Transcription factor | no | HD, Otx2_TF, Otx_TF | |
| PROP1 | Transcription factor | no | HTH_motif, HD, Homeodomain-like_sf |
Expression context
Cohort genes with no expression data: 0.
7 cohort genes are a single-cell marker in ≥1 SCXA experiment.
Breadth distribution (Bgee present_calls)
| Bucket | Genes |
|---|---|
| narrow (1-5 tissues) | 1 |
| moderate (6-20) | 0 |
| broad (>20) | 10 |
| unknown | 0 |
Top tissues across cohort
| Tissue | Cohort genes |
|---|---|
| tendon of biceps brachii | 3 |
| cranial nerve II | 2 |
| left adrenal gland | 1 |
| right adrenal gland | 1 |
| right adrenal gland cortex | 1 |
| hair follicle | 1 |
| ventricular zone | 1 |
| primordial germ cell in gonad | 1 |
| right testis | 1 |
| cervix squamous epithelium | 1 |
| parotid gland | 1 |
| biceps brachii | 1 |
| germinal epithelium of ovary | 1 |
| skeletal muscle tissue of biceps brachii | 1 |
| medial globus pallidus | 1 |
| pancreatic ductal cell | 1 |
| duodenum | 1 |
| heart left ventricle | 1 |
| right atrium auricular region | 1 |
| buccal mucosa cell | 1 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| NR5A1 | 77 | tissue_specific | yes | right adrenal gland cortex, right adrenal gland, left adrenal gland |
| SOX9 | 274 | ubiquitous | marker | ventricular zone, cranial nerve II, hair follicle |
| SRY | 66 | tissue_specific | yes | primordial germ cell in gonad, tendon of biceps brachii, right testis |
| WWOX | 286 | ubiquitous | marker | parotid gland, cervix squamous epithelium, cranial nerve II |
| ZFPM2 | 239 | ubiquitous | marker | skeletal muscle tissue of biceps brachii, germinal epithelium of ovary, biceps brachii |
| DHX37 | 236 | ubiquitous | yes | pancreatic ductal cell, tendon of biceps brachii, medial globus pallidus |
| GATA4 | 85 | broad | marker | right atrium auricular region, heart left ventricle, duodenum |
| MAP3K1 | 264 | ubiquitous | marker | buccal mucosa cell, upper leg skin, skin of hip |
| SOS1 | 289 | ubiquitous | marker | colonic epithelium, jejunal mucosa, tendon of biceps brachii |
| OTX2 | 62 | broad | marker | secondary oocyte, oocyte, pigmented layer of retina |
| PROP1 | 4 | yes | pituitary gland, adenohypophysis, bone marrow cell |
Protein interactions among cohort
Intra-cohort edges: 4.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| WWOX | 5,892 |
| GATA4 | 4,994 |
| SOX9 | 4,935 |
| MAP3K1 | 4,414 |
| SOS1 | 3,625 |
| DHX37 | 3,123 |
| SRY | 2,835 |
| OTX2 | 2,368 |
| NR5A1 | 2,146 |
| ZFPM2 | 1,437 |
Intra-cohort edges
| A | B | Sources |
|---|---|---|
| GATA4 | NR5A1 | biogrid_interaction |
| GATA4 | ZFPM2 | biogrid_interaction, string_interaction |
| NR5A1 | SOX9 | biogrid_interaction, string_interaction |
| NR5A1 | SRY | string_interaction |
Structural data
PDB: 8 · AlphaFold-only: 3 · No structure: 0
Cohort genes with PDB structures (top 30)
| Symbol | UniProt | PDB entries |
|---|---|---|
| SOS1 | Q07889 | 91 |
| SRY | Q05066 | 10 |
| NR5A1 | Q13285 | 6 |
| GATA4 | P43694 | 3 |
| SOX9 | P48436 | 1 |
| WWOX | Q9NZC7 | 1 |
| DHX37 | Q8IY37 | 1 |
| MAP3K1 | Q13233 | 1 |
AlphaFold-only cohort genes (top 30 by pLDDT)
| Symbol | UniProt | pLDDT |
|---|---|---|
| PROP1 | O75360 | 70.74 |
| OTX2 | P32243 | 60.99 |
| ZFPM2 | Q8WW38 | 51.93 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 183. Enrichment computed across 11 evidence-associated genes (10 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 10 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| Pathway | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| Transcriptional regulation of testis differentiation | 5 | 356.9× | 1e-10 | NR5A1, SOX9, SRY, ZFPM2, GATA4 |
| Developmental Lineage of Multipotent Pancreatic Progenitor Cells | 2 | 120.2× | 0.011 | SOX9, GATA4 |
| FCERI mediated MAPK activation | 2 | 69.2× | 0.021 | SOS1, MAP3K1 |
| Developmental Lineage of Pancreatic Acinar Cells | 2 | 60.1× | 0.021 | SOX9, GATA4 |
| Fc epsilon receptor (FCERI) signaling | 2 | 54.4× | 0.021 | SOS1, MAP3K1 |
| Deactivation of the beta-catenin transactivating complex | 2 | 46.6× | 0.022 | SOX9, SRY |
| Developmental Lineage of Pancreatic Ductal Cells | 2 | 45.7× | 0.022 | SOX9, GATA4 |
| Downstream signaling of activated FGFR2 | 1 | 571.0× | 0.036 | SOS1 |
| Downstream signaling of activated FGFR3 | 1 | 571.0× | 0.036 | SOS1 |
| Downstream signaling of activated FGFR4 | 1 | 380.7× | 0.040 | SOS1 |
| Signaling by ERBB2 in Cancer | 1 | 228.4× | 0.040 | SOS1 |
| Signaling by EGFRvIII in Cancer | 1 | 228.4× | 0.040 | SOS1 |
| Formation of lateral plate mesoderm | 1 | 228.4× | 0.040 | GATA4 |
| Signaling by Ligand-Responsive EGFR Variants in Cancer | 1 | 190.3× | 0.040 | SOS1 |
| Signaling by NTRK2 (TRKB) | 1 | 163.1× | 0.040 | SOS1 |
| Signaling by PDGFR in disease | 1 | 163.1× | 0.040 | SOS1 |
| SOS-mediated signalling | 1 | 142.8× | 0.040 | SOS1 |
| IGF1R signaling cascade | 1 | 142.8× | 0.040 | SOS1 |
| Activated NTRK3 signals through RAS | 1 | 126.9× | 0.040 | SOS1 |
| Signaling by EGFR in Cancer | 1 | 114.2× | 0.040 | SOS1 |
| EGFR Transactivation by Gastrin | 1 | 114.2× | 0.040 | SOS1 |
| SHC-related events triggered by IGF1R | 1 | 114.2× | 0.040 | SOS1 |
| Signaling by FGFR3 | 1 | 114.2× | 0.040 | SOS1 |
| Negative regulation of activity of TFAP2 (AP-2) family transcription factors | 1 | 114.2× | 0.040 | WWOX |
| Activated NTRK2 signals through RAS | 1 | 114.2× | 0.040 | SOS1 |
| Signaling by NTRK3 (TRKC) | 1 | 114.2× | 0.040 | SOS1 |
| Signaling by KIT in disease | 1 | 114.2× | 0.040 | SOS1 |
| FLT3 signaling in disease | 1 | 114.2× | 0.040 | SOS1 |
| Formation of the posterior neural plate | 1 | 114.2× | 0.040 | OTX2 |
| IRS-mediated signalling | 1 | 103.8× | 0.040 | SOS1 |
GO biological processes by enrichment
Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 11 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| GO term | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| positive regulation of male gonad development | 5 | 766.0× | 3e-12 | NR5A1, SOX9, SRY, ZFPM2, DHX37 |
| negative regulation of female gonad development | 2 | 766.0× | 2e-04 | NR5A1, ZFPM2 |
| positive regulation of transcription by RNA polymerase II | 7 | 9.5× | 2e-04 | NR5A1, SOX9, SRY, WWOX, ZFPM2, GATA4, OTX2 |
| Sertoli cell differentiation | 2 | 278.6× | 0.001 | NR5A1, SOX9 |
| intestinal epithelial cell differentiation | 2 | 278.6× | 0.001 | SOX9, GATA4 |
| male sex determination | 2 | 255.3× | 0.001 | NR5A1, SRY |
| male gonad development | 3 | 42.6× | 0.001 | NR5A1, SOX9, GATA4 |
| Fc-epsilon receptor signaling pathway | 2 | 133.2× | 0.003 | SOS1, MAP3K1 |
| aortic valve morphogenesis | 2 | 78.6× | 0.008 | SOX9, GATA4 |
| hair follicle development | 2 | 69.6× | 0.009 | SOS1, SOX9 |
| positive regulation of DNA-templated transcription | 4 | 10.2× | 0.010 | SOX9, SRY, GATA4, OTX2 |
| negative regulation of immune system process | 1 | 766.0× | 0.014 | SOX9 |
| right ventricular cardiac muscle tissue morphogenesis | 1 | 766.0× | 0.014 | ZFPM2 |
| atrial septum secundum morphogenesis | 1 | 766.0× | 0.014 | GATA4 |
| primary sex determination | 1 | 766.0× | 0.014 | NR5A1 |
| hypophysis morphogenesis | 1 | 766.0× | 0.014 | PROP1 |
| epithelial cell proliferation involved in prostatic bud elongation | 1 | 766.0× | 0.014 | SOX9 |
| regulation of cell proliferation involved in tissue homeostasis | 1 | 766.0× | 0.014 | SOX9 |
| regulation of branching involved in lung morphogenesis | 1 | 766.0× | 0.014 | SOX9 |
| cell proliferation involved in heart morphogenesis | 1 | 766.0× | 0.014 | SOX9 |
| regulation of epithelial cell proliferation involved in lung morphogenesis | 1 | 766.0× | 0.014 | SOX9 |
| cellular response to transforming growth factor beta stimulus | 2 | 50.2× | 0.014 | SOX9, WWOX |
| epidermal growth factor receptor signaling pathway | 2 | 45.1× | 0.014 | SOS1, SOX9 |
| cellular response to mechanical stimulus | 2 | 39.3× | 0.014 | SOX9, MAP3K1 |
| heart valve formation | 1 | 510.7× | 0.014 | SOX9 |
| neural crest cell fate specification | 1 | 510.7× | 0.014 | SOX9 |
| male germ-line sex determination | 1 | 510.7× | 0.014 | SOX9 |
| embryonic heart tube anterior/posterior pattern specification | 1 | 510.7× | 0.014 | GATA4 |
| intrahepatic bile duct development | 1 | 510.7× | 0.014 | SOX9 |
| bronchus cartilage development | 1 | 510.7× | 0.014 | SOX9 |
Therapeutics
Drug target analysis
Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 9
Druggability breadth: 5 of 11 evidence-associated genes (45%) 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 |
|---|---|
| MAP3K1 | PONATINIB |
| SOS1 | IDARUBICIN |
Top cohort targets by molecule count
| Symbol | Molecules | Max phase |
|---|---|---|
| MAP3K1 | 31 | 4 |
| SOS1 | 5 | 4 |
| NR5A1 | 0 | 0 |
| SOX9 | 0 | 0 |
| SRY | 0 | 0 |
| WWOX | 0 | 0 |
| ZFPM2 | 0 | 0 |
| DHX37 | 0 | 0 |
| GATA4 | 0 | 0 |
| OTX2 | 0 | 0 |
Drugs targeting cohort genes (top 30)
| Molecule | Max phase | Targets in cohort |
|---|---|---|
| PONATINIB | 4 | MAP3K1 |
| SORAFENIB | 4 | MAP3K1 |
| RUXOLITINIB | 4 | MAP3K1 |
| REGORAFENIB | 4 | MAP3K1 |
| BARICITINIB | 4 | MAP3K1 |
| BOSUTINIB | 4 | MAP3K1 |
| TOVORAFENIB | 4 | MAP3K1 |
| RIBOCICLIB | 4 | MAP3K1 |
| PAZOPANIB | 4 | MAP3K1 |
| DASATINIB | 4 | MAP3K1 |
| ERLOTINIB | 4 | MAP3K1 |
| CRIZOTINIB | 4 | MAP3K1 |
| IDARUBICIN | 4 | SOS1 |
| DOXORUBICIN | 4 | SOS1 |
| SOTORASIB | 4 | SOS1 |
| ADAGRASIB | 4 | SOS1 |
| ICOTINIB | 3 | MAP3K1 |
| TESEVATINIB | 3 | MAP3K1 |
| LESTAURTINIB | 3 | MAP3K1 |
| TG100-115 | 2 | MAP3K1 |
| SCH-900776 | 2 | MAP3K1 |
| OSI-632 | 2 | MAP3K1 |
| GOLVATINIB | 2 | MAP3K1 |
| RG-547 | 2 | MAP3K1 |
| DANUSERTIB | 2 | MAP3K1 |
| AT-9283 | 2 | MAP3K1 |
| PELITINIB | 2 | MAP3K1 |
| GSK-461364 | 1 | MAP3K1 |
| KW-2449 | 1 | MAP3K1 |
| AV-412 FREE BASE | 1 | MAP3K1 |
Bioactivity and enzyme data
Enzyme cohort genes (≥1 EC): 1.
Cohort genes with ChEMBL bioactivity (full, sorted by assay count)
| Symbol | Assays | Type breakdown |
|---|---|---|
| SOS1 | 421 | Binding:409, Functional:12 |
| MAP3K1 | 167 | Binding:165, ADMET:1, Functional:1 |
| NR5A1 | 88 | Binding:84, Functional:4 |
| GATA4 | 5 | Binding:5 |
| SOX9 | 3 | Binding:3 |
Cohort enzymes (BRENDA EC)
| Symbol | EC numbers | Names |
|---|---|---|
| MAP3K1 | 2.7.11.25 | mitogen-activated protein kinase kinase kinase |
Cohort genes with high screening signal
≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.
| Symbol | ChEMBL assays |
|---|---|
| MAP3K1 | 167 |
| SOS1 | 421 |
Pharmacogenomics
Cohort genes with a PharmGKB record: 11; 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) |
|---|---|---|
| PONATINIB | 4 | MAP3K1 |
| SORAFENIB | 4 | MAP3K1 |
| RUXOLITINIB | 4 | MAP3K1 |
| REGORAFENIB | 4 | MAP3K1 |
| BARICITINIB | 4 | MAP3K1 |
| BOSUTINIB | 4 | MAP3K1 |
| TOVORAFENIB | 4 | MAP3K1 |
| RIBOCICLIB | 4 | MAP3K1 |
| PAZOPANIB | 4 | MAP3K1 |
| DASATINIB | 4 | MAP3K1 |
| ERLOTINIB | 4 | MAP3K1 |
| CRIZOTINIB | 4 | MAP3K1 |
| IDARUBICIN | 4 | SOS1 |
| DOXORUBICIN | 4 | SOS1 |
| SOTORASIB | 4 | SOS1 |
| ADAGRASIB | 4 | SOS1 |
| ICOTINIB | 3 | MAP3K1 |
| TESEVATINIB | 3 | MAP3K1 |
| LESTAURTINIB | 3 | MAP3K1 |
| TG100-115 | 2 | MAP3K1 |
| SCH-900776 | 2 | MAP3K1 |
| OSI-632 | 2 | MAP3K1 |
| GOLVATINIB | 2 | MAP3K1 |
| RG-547 | 2 | MAP3K1 |
| DANUSERTIB | 2 | MAP3K1 |
| AT-9283 | 2 | MAP3K1 |
| PELITINIB | 2 | MAP3K1 |
| GSK-461364 | 1 | MAP3K1 |
| KW-2449 | 1 | MAP3K1 |
| AV-412 FREE BASE | 1 | MAP3K1 |
Druggability pyramid
Cohort genes binned by druggability tier (high → low):
| Tier | Definition | Genes | Symbols |
|---|---|---|---|
| A | Approved (phase 4 drug) | 2 | MAP3K1, SOS1 |
| B | Phased (≥1) drug, not yet approved | 0 | |
| C | Druggable family + PDB, no drug | 1 | NR5A1 |
| D | Druggable family + AlphaFold only, no drug | 0 | |
| E | Difficult family or no structure, no drug | 8 | SOX9, SRY, WWOX, ZFPM2, DHX37, GATA4, OTX2, PROP1 |
Undrugged target profiles
9 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).
| Symbol | ChEMBL assays | Drugged partners (top 3) |
|---|---|---|
| NR5A1 | 88 | — |
| SOX9 | 3 | — |
| SRY | 0 | — |
| WWOX | 0 | — |
| ZFPM2 | 0 | — |
| DHX37 | 0 | — |
| GATA4 | 5 | — |
| OTX2 | 0 | — |
| PROP1 | 0 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 0.