TFE3

Chr XX-linked

transcription factor binding to IGHM enhancer 3

Also known as: MRXSPF, RCCP2, RCCX1, TFEA, bHLHe33

NCBI Gene: 7030ENSG00000068323UniProt: P19532

This gene encodes a basic helix-loop-helix domain-containing transcription factor that binds MUE3-type E-box sequences in the promoter of genes. The encoded protein promotes the expression of genes downstream of transforming growth factor beta (TGF-beta) signaling. This gene may be involved in chromosomal translocations in renal cell carcinomas and other cancers, resulting in the production of fusion proteins. Translocation partners include PRCC (papillary renal cell carcinoma), NONO (non-POU domain containing, octamer-binding), and ASPSCR1 (alveolar soft part sarcoma chromosome region, candidate 1), among other genes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

Primary Disease Associations & Inheritance

Intellectual developmental disorder, X-linked syndromic, with pigmentary mosaicism and coarse faciesMIM #301066
X-linked
Renal cell carcinoma, papillary, 1MIM #300854
197
ClinVar variants
80
Pathogenic / LP
0.98
pLI score· haploinsufficient
2
Active trials
Clinical Summary— TFE3
🧬
Gene-Disease Validity (ClinGen)
X-linked syndromic complex neurodevelopmental disorder · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
80 Pathogenic / Likely Pathogenic· 89 VUS of 197 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.29LOEUF
pLI 0.980
Z-score 3.52
OE 0.06 (0.02–0.29)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.15Z-score
OE missense 0.60 (0.52–0.69)
140 obs / 232.4 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.06 (0.02–0.29)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.60 (0.52–0.69)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.90
0≤1.21.6
LoF obs/exp: 1 / 16.3Missense obs/exp: 140 / 232.4Syn Z: 0.83

ClinVar Variant Classifications

197 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic69
Likely Pathogenic11
VUS89
Likely Benign24
Benign3
Conflicting1
69
Pathogenic
11
Likely Pathogenic
89
VUS
24
Likely Benign
3
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
9
59
0
69
Likely Pathogenic
0
8
3
0
11
VUS
5
73
11
0
89
Likely Benign
0
14
3
7
24
Benign
0
1
1
1
3
Conflicting
—1
Total6105778197

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

TFE3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

TFE3-related intellectual disability with pigmentary mosaicism and coarse features

definitive
Monoallelic X HeterozygousUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Intellectual developmental disorder, X-linked syndromic, with pigmentary mosaicism and coarse facies

MIM #301066

Molecular basis of disorder known

X-linked

Renal cell carcinoma, papillary, 1

MIM #300854

Molecular basis of disorder known

📖
GeneReview available — TFE3
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The Metabolic Basis of Kidney Cancer.
Linehan WM et al.·Cancer Discov
2019Review
TFEB at a glance.
Napolitano G et al.·J Cell Sci
2016Review
Protein phosphatase 6 regulates metabolic dysfunction-associated steatohepatitis via the mTORC1 pathway.
Liu Z et al.·J Hepatol
2025
PEComa-its clinical features, histopathology, and current therapy.
Izubuchi Y et al.·Jpn J Clin Oncol
2025Review
Clinico-pathological implications of the 2022 WHO Renal Cell Carcinoma classification.
Rizzo M et al.·Cancer Treat Rev
2023Review
Integrating single-nucleus sequence profiling to reveal the transcriptional dynamics of Alzheimer's disease, Parkinson's disease, and multiple sclerosis.
Fan LY et al.·J Transl Med
2023
TFEB and TFE3 drive kidney cystogenesis and tumorigenesis.
Di Malta C et al.·EMBO Mol Med
2023
Perivascular epithelioid cell neoplasms of soft tissue and gynecologic origin: a clinicopathologic study of 26 cases and review of the literature.
Folpe AL et al.·Am J Surg Pathol
2005Review
The AKT2/SIRT5/TFEB pathway as a potential therapeutic target in non-neovascular AMD.
Ghosh S et al.·Nat Commun
2024
Translocation carcinomas of the kidney.
Argani P·Genes Chromosomes Cancer
2022Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
YAP1::TFE3-rearranged inflammatory spindle cell PEComa of the anterior mediastinum in a 5-year-old child: first pediatric case.
Ali RH et al.·Virchows Arch
2026
A Rare Case of TFE3-Rearranged and SMARCB1-Mutated Renal Cell Carcinoma: Diagnostic and Therapeutic Complexities.
Pecorin PJ et al.·Case Rep Oncol Med
2026🔓 Open Access
TFE3 fusion proteins drive TFE3 rearranged renal cell carcinoma progression via PGC-1α-mediated fatty acid oxidation.
Feng F et al.·Front Immunol
2026🔓 Open Access
Tuberous sclerosis complex-associated renal cell carcinoma, an underappreciated form of familial renal cancer, is characterized by activation of the TFEB/TFE3 pathway.
Ricketts CJ et al.·Hum Mol Genet
2026
Hyperactivation of mTORC1 blocks stem cell fate transitions through TFE3-NuRD association.
Li P et al.·EMBO Rep
2026🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Adult Cystic NephromaAnaplastic Kidney Wilms TumorAngiolipoma

Study of Kidney Tumors in Younger Patients

ACTIVE NOT RECRUITING
NCT00898365Children's Oncology GroupStarted 2006-02-27
Cytology Specimen Collection ProcedureLaboratory Biomarker Analysis
Malignant Neoplasms of Urinary TractRenal Cell CarcinomaChromophobe Renal Cell Carcinoma

Cabozantinib or Sunitinib Malate in Treating Participants With Metastatic Variant Histology Renal Cell Carcinoma

ACTIVE NOT RECRUITING
NCT03541902Phase PHASE2M.D. Anderson Cancer CenterStarted 2018-05-15
CabozantinibSunitinib Malate

External Resources

Links to major genomics databases and tools