RNF125

Chr 18AD

ring finger protein 125

Also known as: TNORS, TRAC-1, TRAC1

NCBI Gene: 54941ENSG00000101695UniProt: Q96EQ8

This protein is an E3 ubiquitin ligase that targets proteins for degradation and regulates T-cell activation and interferon signaling pathways. Mutations cause Tenorio syndrome, a multisystem disorder affecting growth, development, and immune function. The condition follows autosomal dominant inheritance.

Summary from RefSeq, OMIM, UniProt
Research Assistant →

Primary Disease Associations & Inheritance

Tenorio syndromeMIM #616260
AD
0
Active trials
14
Pubs (1 yr)
41
P/LP submissions
5%
P/LP missense
1.28
LOEUF
Multiple*
Mechanism· predicted
Clinical Summary— RNF125
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
39 unique Pathogenic / Likely Pathogenic· 71 VUS of 151 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
1.28LOEUF
pLI 0.000
Z-score 0.89
OE 0.71 (0.42–1.28)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
0.78Z-score
OE missense 0.81 (0.69–0.95)
109 obs / 134.6 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.71 (0.42–1.28)
0≤0.351.4
Missense OE0.81 (0.69–0.95)
0≤0.61.4
Synonymous OE0.94
0≤1.21.6
LoF obs/exp: 8 / 11.2Missense obs/exp: 109 / 134.6Syn Z: 0.35
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
limitedRNF125-related intellectual disability and macrocephalyOTHERAD
DN
0.5477th %ile
GOF
0.6443th %ile
LOF
0.3551th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median
LOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

LOFThey demonstrated that haploinsufficiency of RNF125 leads to upregulation of RIGI, IPS1, and MDA5 and to misregulation of the 3 main pathways.PMID:25196541

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

151 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic37
Likely Pathogenic2
VUS71
Likely Benign18
Benign10
Conflicting5
37
Pathogenic
2
Likely Pathogenic
71
VUS
18
Likely Benign
10
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
36
0
37
Likely Pathogenic
0
1
1
0
2
VUS
4
44
23
0
71
Likely Benign
0
4
4
10
18
Benign
0
3
2
5
10
Conflicting
—5
Total4536615143

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

View in ClinVar →

Protein Context — Lollipop Plot

RNF125 · protein map & ClinVar variants

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
RNF125 promotes CD8 T cell-mediated anticancer immunity and suppresses the malignant phenotype of cervical cancer.
Yang D et al.·Mol Cell Biochem
2026
RNF125 suppresses stem cell-like properties and metastasis in non-small cell lung cancer by promoting ubiquitination and degradation of DDX5.
Leng X et al.·Pathol Res Pract
2026
Targeting mTORC2-dependent AKT/FOXO1/RNF125 signaling exploits a therapeutic vulnerability in c-MET-activated and β-catenin-mutated hepatocellular carcinoma.
Wang X et al.·Hepatology
2025
[Reduction in RNF125-mediated RIG-I ubiquitination and degradation promotes renal inflammation and fibrosis progression].
Li LX et al.·Sheng Li Xue Bao
2025
RNA‑binding protein MBNL1 regulates tumor growth, chemosensitivity and antitumor immunity in lung adenocarcinoma by controlling the expression of tumor suppressor RNF125.
Yan Y et al.·Oncol Rep
2025Open Access
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients