46,XX sex reversal 4

Summary

46,XX sex reversal 4 (MONDO:0060489) is a disease caused by NR5A1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: NR5A1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 11

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	46,XX sex reversal 4
Mondo ID	MONDO:0060489
OMIM	617480
DOID	DOID:0111764
UMLS	C4479552
MedGen	1373282
GARD	0025995
Is cancer (heuristic)	no

Also known as: 46, XX sex reversal 4 · SRXX4

Data availability: 11 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 › disorder of sexual differentiation › 46,XX disorder of sex development › 46,XX testicular disorder of sex development › 46,XX sex reversal 4

Related subtypes (3): 46,XX sex reversal 2, 46,XX sex reversal 3, 46,XX sex reversal 1

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:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
1031482	NM_004959.5(NR5A1):c.637_640dup (p.Pro214fs)	NR5A1	Pathogenic	criteria provided, single submitter
12796	NM_004959.5(NR5A1):c.275G>A (p.Arg92Gln)	NR5A1	Pathogenic	no assertion criteria provided
3596432	NM_004959.5(NR5A1):c.247G>A (p.Val83Met)	NR5A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4294444	NM_004959.5(NR5A1):c.529del (p.His177fs)	NR5A1	Likely pathogenic	criteria provided, single submitter
4820221	NM_004959.5(NR5A1):c.779C>T (p.Ala260Val)	NR5A1	Likely pathogenic	criteria provided, single submitter
265792	NM_004959.5(NR5A1):c.274C>T (p.Arg92Trp)	NR5A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
570773	NM_004959.5(NR5A1):c.88T>C (p.Cys30Arg)	NR5A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1302227	NM_004959.5(NR5A1):c.205C>T (p.Arg69Cys)	NR5A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
4796609	NM_004959.5(NR5A1):c.1358T>G (p.Ile453Ser)	NR5A1	Uncertain significance	criteria provided, single submitter
12795	NM_004959.5(NR5A1):c.764G>T (p.Arg255Leu)	NR5A1	Likely benign	criteria provided, single submitter
4819940	NM_004959.5(NR5A1):c.541G>A (p.Ala181Thr)	NR5A1	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 6 · 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

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NR5A1	HGNC:7983	ENSG00000136931	Q13285	Steroidogenic factor 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

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

Protein-family classification

Druggable: 1 · 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
Nuclear receptor	1	385.9×	0.003

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

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

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

Top tissues across cohort

Tissue	Cohort genes
left adrenal gland	1
right adrenal gland	1
right adrenal gland cortex	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NR5A1	2,146

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NR5A1	Q13285	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 1 evidence-associated genes (1 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 1 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	1	713.8×	0.011	NR5A1
Transcriptional regulation of pluripotent stem cells	1	543.8×	0.011	NR5A1
SUMOylation of intracellular receptors	1	335.9×	0.012	NR5A1
Nuclear Receptor transcription pathway	1	200.3×	0.012	NR5A1
SUMO E3 ligases SUMOylate target proteins	1	178.4×	0.012	NR5A1
SUMOylation	1	163.1×	0.012	NR5A1
RNA Polymerase II Transcription	1	22.5×	0.075	NR5A1
Post-translational protein modification	1	19.2×	0.075	NR5A1
Gene expression (Transcription)	1	17.8×	0.075	NR5A1
Generic Transcription Pathway	1	15.1×	0.075	NR5A1
Developmental Biology	1	14.5×	0.075	NR5A1
Metabolism of proteins	1	12.4×	0.081	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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
primary sex determination	1	8426.0×	0.001	NR5A1
response to gonadotropin-releasing hormone	1	5617.3×	0.001	NR5A1
negative regulation of female gonad development	1	4213.0×	0.001	NR5A1
luteinization	1	1872.4×	0.001	NR5A1
tissue development	1	1872.4×	0.001	NR5A1
sex determination	1	1685.2×	0.001	NR5A1
positive regulation of male gonad development	1	1685.2×	0.001	NR5A1
regulation of steroid biosynthetic process	1	1532.0×	0.001	NR5A1
Sertoli cell differentiation	1	1532.0×	0.001	NR5A1
calcineurin-mediated signaling	1	1532.0×	0.001	NR5A1
male sex determination	1	1404.3×	0.001	NR5A1
Leydig cell differentiation	1	1203.7×	0.002	NR5A1
maintenance of protein location in nucleus	1	1123.5×	0.002	NR5A1
hormone metabolic process	1	887.0×	0.002	NR5A1
female gonad development	1	802.5×	0.002	NR5A1
adrenal gland development	1	674.1×	0.002	NR5A1
hormone-mediated signaling pathway	1	401.2×	0.003	NR5A1
male gonad development	1	156.0×	0.008	NR5A1
transcription by RNA polymerase II	1	70.5×	0.016	NR5A1
positive regulation of gene expression	1	38.7×	0.028	NR5A1
positive regulation of transcription by RNA polymerase II	1	14.9×	0.070	NR5A1
regulation of transcription by RNA polymerase II	1	11.7×	0.086	NR5A1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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

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

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NR5A1	88	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.