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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.
USP9X
ubiquitin specific peptidase 9 X-linked
Chromosome X Β· Xp11.4
NCBI Gene: 8239Ensembl: ENSG00000124486.15HGNC: HGNC:12632UniProt: A0A994J4R6
355PubMed Papers
22Diseases
0Drugs
129Pathogenic Variants
FUNCTIONAL ROLE
Highly ConstrainedProtease
RESEARCH IMPACT
Highly StudiedTrendingVariant-Rich
CLINICAL
OMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
protein deubiquitination involved in ubiquitin-dependent protein catabolic processpositive regulation of TORC2 signalingcytoplasmgrowth coneintellectual disability, X-linked 99, syndromic, female-restrictedintellectual disability, X-linked 99X-linked non-syndromic intellectual disabilitygenetic disorder
✦AI Summary

USP9X is an X-linked deubiquitinase that plays essential roles in cellular homeostasis and development by removing ubiquitin conjugates from target proteins. The enzyme exhibits substrate specificity, primarily cleaving K63-linked, K48-linked, and K11-linked polyubiquitin chains to regulate protein stability and function 1. USP9X is critical for TGF-Ξ²/BMP signaling through deubiquitination of SMAD4 and regulation of transforming growth factor Ξ² pathways 23. In the cardiovascular system, USP9X suppresses atherosclerosis by deubiquitinating scavenger receptor SR-A1 at K27, reducing foam cell formation 1, and protects against cardiac hypertrophy through MCL1 stabilization and mitochondrial homeostasis 4. The protein is essential for CNS development and function, regulating Wnt signaling via Ξ²-catenin deubiquitination to maintain vascular barrier integrity 5. USP9X also controls Nrf2 stability to prevent ferroptosis in diabetic kidney disease 6. Disease-associated variants cause intellectual developmental disorders in both males and females, with males showing distinctive neurodevelopmental phenotypes including white matter abnormalities, speech delays, and behavioral changes 2. The enzyme's diverse substrate specificity underlies its involvement in metabolic disorders, cancer radioresistance, and neurodegeneration 73.

Sources cited
1
USP9X removes K63 polyubiquitin chains from SR-A1 at K27 site and suppresses atherosclerosis
PMID: 35389885
2
USP9X variants cause neurodevelopmental disorders in males through disrupted TGF-Ξ² signaling
PMID: 31443933
3
USP9X deubiquitinates and stabilizes KDM4C, promoting lung cancer radioresistance via TGF-Ξ²2 signaling
PMID: 33558705
4
USP9X stabilizes MCL1 through deubiquitination, protecting against cardiac hypertrophy
PMID: 40912071
5
USP9X deubiquitinates Ξ²-catenin to regulate Wnt signaling in CNS vascular development
PMID: 39909046
6
USP9X deubiquitinates Nrf2 to prevent ferroptosis in diabetic kidney disease
PMID: 39967230
7
USP9X is involved in various metabolic disorders through deubiquitination mechanisms
PMID: 36834633
Disease Associationsβ“˜22
intellectual disability, X-linked 99, syndromic, female-restrictedOpen Targets
0.81Strong
intellectual disability, X-linked 99Open Targets
0.71Strong
X-linked non-syndromic intellectual disabilityOpen Targets
0.71Strong
genetic disorderOpen Targets
0.53Moderate
Intellectual disabilityOpen Targets
0.41Moderate
X-linked syndromic intellectual disabilityOpen Targets
0.37Weak
non-syndromic X-linked intellectual disabilityOpen Targets
0.37Weak
polydactylyOpen Targets
0.37Weak
neurodegenerative diseaseOpen Targets
0.32Weak
Neurodevelopmental disorderOpen Targets
0.30Weak
hyperpigmentation of the skinOpen Targets
0.27Weak
Neurodevelopmental abnormalityOpen Targets
0.27Weak
Severe intellectual disabilityOpen Targets
0.26Weak
hepatocellular carcinomaOpen Targets
0.25Weak
nasopharyngeal neoplasmOpen Targets
0.24Weak
prostate adenocarcinomaOpen Targets
0.22Weak
melanomaOpen Targets
0.21Weak
non-small cell lung carcinomaOpen Targets
0.21Weak
acute myeloid leukemiaOpen Targets
0.20Weak
esophageal squamous cell carcinomaOpen Targets
0.20Weak
Intellectual developmental disorder, X-linked 99UniProt
Intellectual developmental disorder, X-linked 99, syndromic, female-restrictedUniProt
Pathogenic Variants129
NM_001039591.3(USP9X):c.2746C>T (p.Arg916Ter)Pathogenic
Intellectual disability, X-linked 99, syndromic, female-restricted|not provided
β˜…β˜…β˜†β˜†2025β†’ Residue 916
NM_001039591.3(USP9X):c.82dup (p.Leu28fs)Pathogenic
not provided|Inborn genetic diseases|USP9X-related disorder
β˜…β˜…β˜†β˜†2025β†’ Residue 28
NM_001039591.3(USP9X):c.3986G>A (p.Arg1329His)Likely pathogenic
not provided
β˜…β˜…β˜†β˜†2024β†’ Residue 1329
NM_001039591.3(USP9X):c.1812_1815del (p.Gln605fs)Pathogenic
Intellectual disability, X-linked 99, syndromic, female-restricted|not provided|USP9X-related disorder
β˜…β˜…β˜†β˜†2023β†’ Residue 605
NM_001039591.3(USP9X):c.7096C>T (p.Arg2366Ter)Pathogenic
Intellectual disability, X-linked 99, syndromic, female-restricted
β˜…β˜…β˜†β˜†2023β†’ Residue 2366
NM_001039591.3(USP9X):c.6254G>A (p.Arg2085His)Pathogenic
Intellectual disability, X-linked 99|not provided
β˜…β˜…β˜†β˜†2023β†’ Residue 2085
NM_001039591.3(USP9X):c.323-1G>APathogenic
Intellectual disability, X-linked 99, syndromic, female-restricted|Intellectual disability, X-linked 99
β˜…β˜…β˜†β˜†2023
NM_001039591.3(USP9X):c.2248C>T (p.Arg750Ter)Pathogenic
not provided
β˜…β˜†β˜†β˜†2026β†’ Residue 750
NM_001039591.3(USP9X):c.7306C>T (p.Gln2436Ter)Pathogenic
Intellectual disability, X-linked 99, syndromic, female-restricted
β˜…β˜†β˜†β˜†2025β†’ Residue 2436
NM_001039591.3(USP9X):c.1618dup (p.Cys540fs)Likely pathogenic
Intellectual disability, X-linked 99
β˜…β˜†β˜†β˜†2025β†’ Residue 540
NM_001039591.3(USP9X):c.2644_2645insA (p.Arg882fs)Pathogenic
Intellectual disability, X-linked 99, syndromic, female-restricted
β˜…β˜†β˜†β˜†2025β†’ Residue 882
NM_001039591.3(USP9X):c.6045dup (p.Leu2016fs)Pathogenic
Intellectual disability, X-linked 99, syndromic, female-restricted
β˜…β˜†β˜†β˜†2025β†’ Residue 2016
NM_001039591.3(USP9X):c.6181_6184del (p.Lys2060_Lys2061insTer)Pathogenic
not provided
β˜…β˜†β˜†β˜†2025β†’ Residue 2060
NM_001039591.3(USP9X):c.7522C>T (p.Gln2508Ter)Likely pathogenic
not provided
β˜…β˜†β˜†β˜†2025β†’ Residue 2508
NM_001039591.3(USP9X):c.1774C>T (p.Arg592Ter)Pathogenic
not provided
β˜…β˜†β˜†β˜†2025β†’ Residue 592
NM_001039591.3(USP9X):c.6969dup (p.Gln2324fs)Pathogenic
not provided
β˜…β˜†β˜†β˜†2025β†’ Residue 2324
NM_001039591.3(USP9X):c.5645_5647del (p.Ser1882del)Likely pathogenic
Intellectual disability, X-linked 99, syndromic, female-restricted
β˜…β˜†β˜†β˜†2025β†’ Residue 1882
NM_001039591.3(USP9X):c.3278_3279del (p.Glu1093fs)Pathogenic
not provided
β˜…β˜†β˜†β˜†2025β†’ Residue 1093
NM_001039591.3(USP9X):c.3435_3437dup (p.Gly1146_Ala1147insGly)Likely pathogenic
not provided
β˜…β˜†β˜†β˜†2025β†’ Residue 1146
NM_001039591.3(USP9X):c.1333A>G (p.Ile445Val)Likely pathogenic
Intellectual disability, X-linked 99
β˜…β˜†β˜†β˜†2025β†’ Residue 445
View on ClinVar β†—
Related Genes
UBCProtein interaction100%CTNNB1Protein interaction100%SMAD4Protein interaction97%MCL1Protein interaction96%SNCAProtein interaction94%HUWE1Protein interaction91%
Tissue Expression6 tissues
Brain
100%
Heart
60%
Lung
53%
Bone Marrow
47%
Liver
46%
Ovary
39%
Gene Interaction Network
Click a node to explore
USP9XUBCCTNNB1SMAD4MCL1SNCAHUWE1
PROTEIN STRUCTURE
Preparing viewer…
PDB5VBD Β· 1.50 Γ… Β· X-ray
View on RCSB β†—
Constraintβ“˜
LOEUFβ“˜
0.07Highly Constrained
pLIβ“˜
1.00Intolerant
Observed/Expected LoF0.04 [0.02–0.07]
RankingsWhere USP9X stands among ~20K protein-coding genes
  • #873of 20,598
    Most Researched355 Β· top 5%
  • #597of 5,498
    Most Pathogenic Variants129 Β· top quartile
  • #15of 17,882
    Most Constrained (LOEUF)0.07 Β· top 1%
Genes detectedUSP9X
Sources retrieved27 papers
Response timeβ€”
πŸ“„ Sources
27β–Ό
1
Ubiquitin-Specific Proteases (USPs) and Metabolic Disorders.
PMID: 36834633
Int J Mol Sci Β· 2023
1.00
2
Disruption of USP9X in macrophages promotes foam cell formation and atherosclerosis.
PMID: 35389885
J Clin Invest Β· 2022
0.90
3
USP9X-mediated KDM4C deubiquitination promotes lung cancer radioresistance by epigenetically inducing TGF-Ξ²2 transcription.
PMID: 33558705
Cell Death Differ Β· 2021
0.80
4
Protein Phosphatase 1 Subunit PPP1R14B Stabilizes STMN1 to Promote Progression and Paclitaxel Resistance in Triple-Negative Breast Cancer.
PMID: 36484700
Cancer Res Β· 2023
0.76
5
Tectorigenin attenuates cardiac hypertrophy via USP9X/MCL1-mediated mitochondrial stabilization.
PMID: 40912071
Redox Biol Β· 2025
0.70