46,XY sex reversal 3

Summary

46,XY sex reversal 3 (MONDO:0013066) is a disease caused by NR5A1 (GenCC Strong), with 3 cohort genes. The dominant Reactome pathway is Transcriptional regulation of testis differentiation (3 cohort genes).

At a glance

• Causal gene: NR5A1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 86

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	46,XY sex reversal 3
Mondo ID	MONDO:0013066
OMIM	612965
DOID	DOID:0111772
UMLS	C3489793
MedGen	483746
GARD	0015598
Is cancer (heuristic)	no

Also known as: 46,XY sex reversal 3 · 46,XY Sex reversal type 3 · 46XY sex reversal 3 · SRXY3

Data availability: 86 ClinVar variants · 1 GenCC gene-disease record.

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 sex reversal 3

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 5, 46,XY sex reversal 6, 46,XY disorder of sex development due to testicular 17,20-desmolase deficiency, 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

86 retrieved; paginated sample, class counts are floors:

31 pathogenic, 18 likely pathogenic, 16 uncertain significance, 6 pathogenic/likely pathogenic, 5 conflicting classifications of pathogenicity, 4 benign, 3 benign/likely benign, 3 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
805889	NM_001308093.3(GATA4):c.687G>C (p.Trp229Cys)	GATA4	Pathogenic	no assertion criteria provided
1202586	NM_004959.5(NR5A1):c.244+1G>T	NR5A1	Pathogenic	criteria provided, single submitter
1256011	NM_004959.5(NR5A1):c.250C>T (p.Arg84Cys)	NR5A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12794	NM_004959.5(NR5A1):c.104_105delinsAA (p.Gly35Glu)	NR5A1	Pathogenic	no assertion criteria provided
12796	NM_004959.5(NR5A1):c.275G>A (p.Arg92Gln)	NR5A1	Pathogenic	no assertion criteria provided
12797	NM_004959.5(NR5A1):c.1058_1065del (p.Glu353fs)	NR5A1	Pathogenic	no assertion criteria provided
12798	NM_004959.5(NR5A1):c.48C>A (p.Cys16Ter)	NR5A1	Pathogenic	no assertion criteria provided
12799	NM_004959.5(NR5A1):c.18del (p.Asp6fs)	NR5A1	Pathogenic	no assertion criteria provided
12800	NM_004959.5(NR5A1):c.43G>A (p.Val15Met)	NR5A1	Pathogenic	no assertion criteria provided
12801	NM_004959.5(NR5A1):c.234G>A (p.Met78Ile)	NR5A1	Pathogenic	no assertion criteria provided
12803	NM_004959.5(NR5A1):c.1310T>A (p.Leu437Gln)	NR5A1	Pathogenic	no assertion criteria provided
12804	NM_004959.5(NR5A1):c.666del (p.Asn222fs)	NR5A1	Pathogenic	no assertion criteria provided
12805	NM_004959.5(NR5A1):c.877G>A (p.Asp293Asn)	NR5A1	Pathogenic	no assertion criteria provided
12806	NM_004959.5(NR5A1):c.3G>A (p.Met1Ile)	NR5A1	Pathogenic	no assertion criteria provided
12807	NM_004959.5(NR5A1):c.390del (p.Pro131fs)	NR5A1	Pathogenic	no assertion criteria provided
1341694	NM_004959.5(NR5A1):c.19G>T (p.Glu7Ter)	NR5A1	Pathogenic	criteria provided, single submitter
1342834	NM_004959.5(NR5A1):c.1048C>T (p.Arg350Trp)	NR5A1	Pathogenic	no assertion criteria provided
1442980	NM_004959.5(NR5A1):c.86C>T (p.Thr29Met)	NR5A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1687524	NM_004959.5(NR5A1):c.11C>A (p.Ser4Ter)	NR5A1	Pathogenic	criteria provided, single submitter
1687572	NM_004959.5(NR5A1):c.259C>T (p.Arg87Cys)	NR5A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1699288	NM_004959.5(NR5A1):c.983G>T (p.Gly328Val)	NR5A1	Pathogenic	criteria provided, single submitter
1805655	NM_004959.5(NR5A1):c.164del (p.Cys55fs)	NR5A1	Pathogenic	criteria provided, single submitter
2092105	NM_004959.5(NR5A1):c.1106_1109del (p.Val369fs)	NR5A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
216975	NM_004959.5(NR5A1):c.151G>T (p.Glu51Ter)	NR5A1	Pathogenic	criteria provided, single submitter
216976	NM_004959.5(NR5A1):c.1210T>G (p.Tyr404Asp)	NR5A1	Pathogenic	criteria provided, single submitter
2572556	NM_004959.5(NR5A1):c.15C>A (p.Tyr5Ter)	NR5A1	Pathogenic	criteria provided, single submitter
3235911	NM_004959.5(NR5A1):c.841C>T (p.Arg281Cys)	NR5A1	Pathogenic	criteria provided, single submitter
3596432	NM_004959.5(NR5A1):c.247G>A (p.Val83Met)	NR5A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372437	NM_004959.5(NR5A1):c.937C>T (p.Arg313Cys)	NR5A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3895489	NM_004959.5(NR5A1):c.1114_1116del (p.Lys372del)	NR5A1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 17 · 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
NR5A1	Strong	Autosomal dominant	46,XY sex reversal 3	12

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
ZFPM2	Orphanet:2140	Congenital diaphragmatic hernia
ZFPM2	Orphanet:251510	46,XY partial gonadal dysgenesis
ZFPM2	Orphanet:3303	Tetralogy of Fallot
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

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
NR5A1	HGNC:7983	ENSG00000136931	Q13285	Steroidogenic factor 1	gencc,clinvar
ZFPM2	HGNC:16700	ENSG00000169946	Q8WW38	Zinc finger protein ZFPM2	clinvar
GATA4	HGNC:4173	ENSG00000136574	P43694	Transcription factor GATA-4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NR5A1	Steroidogenic factor 1	Transcriptional activator.
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.
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.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 0 · Druggable fraction: 0.33

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×	0.016
Transcription factor	2	5.5×	0.040

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
ZFPM2	Transcription factor	no		Znf_C2H2_type, Znf_CCHC_FOG, Znf_C2H2_sf
GATA4	Transcription factor	no		Znf_GATA, GATA_N, Znf_NHR/GATA

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
left adrenal gland	1
right adrenal gland	1
right adrenal gland cortex	1
biceps brachii	1
germinal epithelium of ovary	1
skeletal muscle tissue of biceps brachii	1
duodenum	1
heart left ventricle	1
right atrium auricular region	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
ZFPM2	239	ubiquitous	marker	skeletal muscle tissue of biceps brachii, germinal epithelium of ovary, biceps brachii
GATA4	85	broad	marker	right atrium auricular region, heart left ventricle, duodenum

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GATA4	4,994
NR5A1	2,146
ZFPM2	1,437

Intra-cohort edges

A	B	Sources
GATA4	NR5A1	biogrid_interaction
GATA4	ZFPM2	biogrid_interaction, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NR5A1	Q13285	6
GATA4	P43694	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ZFPM2	Q8WW38	51.93

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. 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
Transcriptional regulation of testis differentiation	3	713.8×	5e-08	NR5A1, ZFPM2, GATA4
Factors involved in megakaryocyte development and platelet production	2	44.3×	0.007	ZFPM2, GATA4
Formation of lateral plate mesoderm	1	761.3×	0.010	GATA4
Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP)	1	292.8×	0.013	GATA4
YAP1- and WWTR1 (TAZ)-stimulated gene expression	1	253.8×	0.013	GATA4
Formation of definitive endoderm	1	237.9×	0.013	GATA4
Physiological factors	1	223.9×	0.013	GATA4
Developmental Lineage of Multipotent Pancreatic Progenitor Cells	1	200.3×	0.013	GATA4
Transcriptional regulation of pluripotent stem cells	1	181.3×	0.013	NR5A1
Cardiogenesis	1	141.0×	0.016	GATA4
SUMOylation of intracellular receptors	1	112.0×	0.018	NR5A1
Developmental Lineage of Pancreatic Acinar Cells	1	100.2×	0.018	GATA4
Developmental Lineage of Pancreatic Ductal Cells	1	76.1×	0.022	GATA4
Nuclear Receptor transcription pathway	1	66.8×	0.023	NR5A1
SUMO E3 ligases SUMOylate target proteins	1	59.5×	0.025	NR5A1
SUMOylation	1	54.4×	0.025	NR5A1
RNA Polymerase II Transcription	1	7.5×	0.165	NR5A1
Post-translational protein modification	1	6.4×	0.181	NR5A1
Gene expression (Transcription)	1	6.0×	0.184	NR5A1
Generic Transcription Pathway	1	5.0×	0.203	NR5A1
Developmental Biology	1	4.8×	0.203	NR5A1
Metabolism of proteins	1	4.1×	0.223	NR5A1

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
negative regulation of female gonad development	2	2808.7×	9e-06	NR5A1, ZFPM2
positive regulation of male gonad development	2	1123.5×	3e-05	NR5A1, ZFPM2
male gonad development	2	104.0×	0.003	NR5A1, GATA4
right ventricular cardiac muscle tissue morphogenesis	1	2808.7×	0.004	ZFPM2
atrial septum secundum morphogenesis	1	2808.7×	0.004	GATA4
primary sex determination	1	2808.7×	0.004	NR5A1
positive regulation of transcription by RNA polymerase II	3	14.9×	0.004	NR5A1, ZFPM2, GATA4
embryonic heart tube anterior/posterior pattern specification	1	1872.4×	0.004	GATA4
response to gonadotropin-releasing hormone	1	1872.4×	0.004	NR5A1
atrioventricular valve formation	1	1404.3×	0.005	GATA4
cardiac muscle tissue regeneration	1	1404.3×	0.005	GATA4
atrial septum primum morphogenesis	1	1123.5×	0.005	GATA4
atrioventricular node development	1	936.2×	0.005	GATA4
cell growth involved in cardiac muscle cell development	1	802.5×	0.005	GATA4
transdifferentiation	1	702.2×	0.005	GATA4
luteinization	1	624.1×	0.005	NR5A1
cardiac ventricle morphogenesis	1	624.1×	0.005	GATA4
tissue development	1	624.1×	0.005	NR5A1
gonadal mesoderm development	1	561.7×	0.005	ZFPM2
sex determination	1	561.7×	0.005	NR5A1
embryonic foregut morphogenesis	1	561.7×	0.005	GATA4
atrioventricular canal development	1	510.7×	0.005	GATA4
regulation of steroid biosynthetic process	1	510.7×	0.005	NR5A1
Sertoli cell differentiation	1	510.7×	0.005	NR5A1
intestinal epithelial cell differentiation	1	510.7×	0.005	GATA4
calcineurin-mediated signaling	1	510.7×	0.005	NR5A1
endocardial cushion development	1	468.1×	0.005	GATA4
cardiac right ventricle morphogenesis	1	468.1×	0.005	GATA4
male sex determination	1	468.1×	0.005	NR5A1
atrial septum morphogenesis	1	432.1×	0.006	GATA4

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NR5A1	0	0
ZFPM2	0	0
GATA4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NR5A1	88	Binding:84, Functional:4
GATA4	5	Binding:5

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

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	2	ZFPM2, GATA4

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)
NR5A1	88	—
ZFPM2	0	—
GATA4	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.