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GeneE
27 sources retrieved Β· Most recent: April 2026 Β· Index updated 14 days ago
β“˜GeneE is for informational purposes only. It is not a substitute for professional medical advice, diagnosis, or treatment.
NR5A1
nuclear receptor subfamily 5 group A member 1
Chromosome 9 Β· 9q33.3
NCBI Gene: 2516Ensembl: ENSG00000136931.11HGNC: HGNC:7983UniProt: F1D8R8
290PubMed Papers
25Diseases
0Drugs
129Pathogenic Variants
FUNCTIONAL ROLE
Highly ConstrainedReceptorTranscription Factor
RESEARCH IMPACT
TrendingVariant-Rich
CLINICAL
OMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
RNA polymerase II transcription regulatory region sequence-specific DNA bindingDNA-binding transcription activator activitytranscription coregulator bindingDNA binding46,XY sex reversal 3premature ovarian failure 7spermatogenic failure 8primary ovarian insufficiency
✦AI Summary

NR5A1 (steroidogenic factor 1) is a nuclear receptor transcription factor essential for sexual differentiation and steroidogenic tissue development 1. It functions by binding to specific DNA consensus sequences (5'-YCAAGGYC-3' and 5'-RRAGGTCA-3') in promoter regions of steroidogenic genes including CYP11A, CYP11B, CYP21A, and CYP17, regulating basal and cAMP-dependent transcription 1. NR5A1 also regulates genes controlling anti-MΓΌllerian hormone, adrenal steroidogenesis, and gonadal development. The protein is activated through phosphorylation by HIPK3, enhancing steroidogenic gene expression via cAMP signaling 1. Functionally, NR5A1 interacts with chr9 remodeling complexes and serves as a molecular adapter linking Ξ²-catenin to BAF/SWI-SNF machinery for site-specific DNA accessibility 2. NR5A1 mutations cause a spectrum of disorders of sex development (DSD), ranging from 46,XY testicular dysgenesis to 46,XX gonadal dysgenesis 3. Loss-of-function variants are associated with primary ovarian insufficiency, hypogonadism, and male infertility 4. Emerging evidence indicates broader impacts beyond reproduction, including effects on metabolic health and spleen function 5. NR5A1 was the most frequently mutated gene in a male infertility cohort, identified in 12% of patients with spermatogenic failure 6. Clinical phenotypes vary significantly even among carriers of identical mutations, complicating genotype-phenotype correlation 3. Early genetic testing during the neonatal period is recommended when gonadal dysgenesis is suspected.

Sources cited
1
NR5A1 is essential for sexual differentiation and steroidogenic tissue formation; binds consensus sequences in steroidogenic P450 gene promoters; activated by HIPK3 phosphorylation
PMID: 27378692
2
Ξ²-catenin serves as molecular adapter linking NR5A1 to BAF chromatin remodeling complex ARID1A for DNA accessibility
PMID: 40695292
3
NR5A1 mutations cause disorders of sex development in both 46,XY and 46,XX individuals; loss of function causes gonadal dysgenesis, hypogonadism, and infertility; clinical phenotypes vary without clear genotype-phenotype correlation
PMID: 38785542
4
NR5A1 mutations associated with wide phenotypic spectrum of DSD in both 46,XY and 46,XX karyotypes, and male infertility; comprehensive review of 188 mutations from 238 cases
PMID: 31513305
5
NR5A1 was most frequently affected gene in male infertility cohort, with 7 pathogenic variants identified in spermatogenic failure patients; molecular diagnosis reached in 12% of SPGF cases
PMID: 38614076
6
NR5A1/SF-1 variants cause 46,XY and 46,XX DSD and primary ovarian insufficiency; emerging evidence suggests broader effects on spleen function and metabolic health beyond gonadal dysfunction
PMID: 40645834
Disease Associationsβ“˜25
46,XY sex reversal 3Open Targets
0.80Strong
premature ovarian failure 7Open Targets
0.77Strong
spermatogenic failure 8Open Targets
0.76Strong
primary ovarian insufficiencyOpen Targets
0.69Moderate
46,XX testicular disorder of sex developmentOpen Targets
0.68Moderate
spermatogenic failure 1Open Targets
0.56Moderate
male infertility with azoospermia or oligozoospermia due to single gene mutationOpen Targets
0.55Moderate
46,XY disorder of sex developmentOpen Targets
0.55Moderate
disorder of sexual differentiationOpen Targets
0.51Moderate
genetic non-acquired premature ovarian failureOpen Targets
0.49Moderate
Genetic 46,XY disorder of sex developmentOpen Targets
0.49Moderate
azoospermiaOpen Targets
0.47Moderate
46,XX ovotesticular disorder of sex developmentOpen Targets
0.47Moderate
46,XY partial gonadal dysgenesisOpen Targets
0.46Moderate
male infertilityOpen Targets
0.40Moderate
46,XX gonadal dysgenesisOpen Targets
0.39Weak
46,XY complete gonadal dysgenesisOpen Targets
0.39Weak
Cytomegalic congenital adrenal hypoplasiaOpen Targets
0.38Weak
X-linked adrenal hypoplasia congenitaOpen Targets
0.38Weak
46 XX gonadal dysgenesisOpen Targets
0.38Weak
46,XX sex reversal 4UniProt
46,XY sex reversal 3UniProt
Adrenal insufficiency, NR5A1-relatedUniProt
Premature ovarian failure 7UniProt
Spermatogenic failure 8UniProt
Pathogenic Variants129
NM_004959.5(NR5A1):c.250C>T (p.Arg84Cys)Pathogenic
Genetic non-acquired premature ovarian failure|46,XY sex reversal 3|not provided|Oligosynaptic infertility;46,XY disorder of sex development
β˜…β˜…β˜†β˜†2026β†’ Residue 84
NM_004959.5(NR5A1):c.251G>A (p.Arg84His)Pathogenic
46,XY sex reversal 3|46,XY disorder of sex development;Oligosynaptic infertility|NR5A1-related disorder
β˜…β˜…β˜†β˜†2025β†’ Residue 84
NM_004959.5(NR5A1):c.64G>A (p.Gly22Ser)Pathogenic
Oligosynaptic infertility;46,XY disorder of sex development|not provided
β˜…β˜…β˜†β˜†2025β†’ Residue 22
NM_004959.5(NR5A1):c.937C>T (p.Arg313Cys)Pathogenic
not provided|46,XY sex reversal 3|Genetic non-acquired premature ovarian failure|Oligosynaptic infertility;46,XY disorder of sex development
β˜…β˜…β˜†β˜†2025β†’ Residue 313
NM_004959.5(NR5A1):c.247G>A (p.Val83Met)Pathogenic
46,XY sex reversal 3;Premature ovarian failure 7;Spermatogenic failure 8;46,XX sex reversal 4|Oligosynaptic infertility;46,XY disorder of sex development
β˜…β˜…β˜†β˜†2024β†’ Residue 83
NM_004959.5(NR5A1):c.86C>T (p.Thr29Met)Pathogenic
46,XY sex reversal 3|46,XY disorder of sex development;Oligosynaptic infertility
β˜…β˜…β˜†β˜†2024β†’ Residue 29
NM_004959.5(NR5A1):c.129CAA[1] (p.Asn44del)Pathogenic
Oligosynaptic infertility;46,XY disorder of sex development|not provided
β˜…β˜…β˜†β˜†2024β†’ Residue 44
NM_004959.5(NR5A1):c.871-1G>CPathogenic
NR5A1-related disorder|not provided
β˜…β˜…β˜†β˜†2024
NM_004959.5(NR5A1):c.1106_1109del (p.Val369fs)Pathogenic
Oligosynaptic infertility;46,XY disorder of sex development|46,XY sex reversal 3|NR5A1-related disorder
β˜…β˜…β˜†β˜†2023β†’ Residue 369
NM_004959.5(NR5A1):c.334C>T (p.Gln112Ter)Pathogenic
Oligosynaptic infertility;46,XY disorder of sex development|Male infertility with azoospermia or oligozoospermia due to single gene mutation
β˜…β˜…β˜†β˜†2023β†’ Residue 112
NM_004959.5(NR5A1):c.259C>T (p.Arg87Cys)Pathogenic
46,XY sex reversal 3|46,XY disorder of sex development;Oligosynaptic infertility|NR5A1-related disorder
β˜…β˜…β˜†β˜†2023β†’ Residue 87
NM_004959.5(NR5A1):c.398del (p.Pro133fs)Pathogenic
not provided|Oligosynaptic infertility;46,XY disorder of sex development
β˜…β˜…β˜†β˜†2022β†’ Residue 133
NM_004959.5(NR5A1):c.990G>A (p.Glu330=)Likely pathogenic
46,XY sex reversal 3|Non-obstructive azoospermia
β˜…β˜…β˜†β˜†2022β†’ Residue 330
NM_004959.5(NR5A1):c.938G>A (p.Arg313His)Pathogenic
not provided|Genetic non-acquired premature ovarian failure|Oligosynaptic infertility;46,XY disorder of sex development
β˜…β˜…β˜†β˜†2021β†’ Residue 313
NM_004959.5(NR5A1):c.415del (p.Val139fs)Pathogenic
46,XY disorder of sex development;Oligosynaptic infertility
β˜…β˜†β˜†β˜†2026β†’ Residue 139
NM_004959.5(NR5A1):c.319C>T (p.Gln107Ter)Pathogenic
46,XY disorder of sex development;Oligosynaptic infertility
β˜…β˜†β˜†β˜†2025β†’ Residue 107
NM_004959.5(NR5A1):c.380_870+39delLikely pathogenic
46,XY disorder of sex development;Oligosynaptic infertility
β˜…β˜†β˜†β˜†2025
NM_004959.5(NR5A1):c.119_120insACGTGCAGAACACGTGTGCA (p.Val41fs)Pathogenic
Differences in sex development
β˜…β˜†β˜†β˜†2025β†’ Residue 41
NM_004959.5(NR5A1):c.833del (p.Asp278fs)Pathogenic
46,XY disorder of sex development;Oligosynaptic infertility
β˜…β˜†β˜†β˜†2025β†’ Residue 278
NM_004959.5(NR5A1):c.340C>T (p.Arg114Trp)Likely pathogenic
46,XY sex reversal 3
β˜…β˜†β˜†β˜†2025β†’ Residue 114
View on ClinVar β†—
Related Genes
HSD3B1Protein interaction100%HSD3B2Protein interaction99%NRIP1Protein interaction99%CTNNB1Protein interaction98%CYP11B1Protein interaction96%CYP11B2Protein interaction96%
Tissue Expression6 tissues
Ovary
100%
Bone Marrow
0%
Liver
0%
Lung
0%
Brain
0%
Heart
0%
Gene Interaction Network
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NR5A1HSD3B1HSD3B2NRIP1CTNNB1CYP11B1CYP11B2
PROTEIN STRUCTURE
Preparing viewer…
PDB1ZDT Β· 2.10 Γ… Β· X-ray
View on RCSB β†—
Constraintβ“˜
LOEUFβ“˜
0.31Highly Constrained
pLIβ“˜
1.00Intolerant
Observed/Expected LoF0.16 [0.09–0.31]
RankingsWhere NR5A1 stands among ~20K protein-coding genes
  • #1,232of 20,598
    Most Researched290 Β· top 10%
  • #598of 5,498
    Most Pathogenic Variants129 Β· top quartile
  • #1,243of 17,882
    Most Constrained (LOEUF)0.31 Β· top 10%
Genes detectedNR5A1
Sources retrieved27 papers
Response timeβ€”
πŸ“„ Sources
27β–Ό
1
Broader impact and outcome of human NR5A1/SF1 variants.
PMID: 40645834
Best Pract Res Clin Endocrinol Metab Β· 2025
1.00
2
Role of
PMID: 38785542
Curr Issues Mol Biol Β· 2024
0.90
3
FOXL2 and NR5A1 induce human fibroblasts into steroidogenic ovarian granulosa-like cells.
PMID: 38192172
Cell Prolif Β· 2024
0.80
4
Mutation update for the NR5A1 gene involved in DSD and infertility.
PMID: 31513305
Hum Mutat Β· 2020
0.80
5
Toward clinical exomes in diagnostics and management of male infertility.
PMID: 38614076
Am J Hum Genet Β· 2024
0.70