RNF40

Chr 16

ring finger protein 40

Also known as: BRE1B, RBP95, STARING

NCBI Gene: 9810ENSG00000103549UniProt: O75150

The protein encoded by this gene contains a RING finger, a motif known to be involved in protein-protein and protein-DNA interactions. This protein was reported to interact with the tumor suppressor protein RB1. Studies of the rat counterpart suggested that this protein may function as an E3 ubiquitin-protein ligase, and facilitate the ubiquitination and degradation of syntaxin 1, which is an essential component of the neurotransmitter release machinery. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2011]

147
ClinVar variants
10
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— RNF40
🧬
Gene-Disease Validity (ClinGen)
congenital heart disease · ADLimited

Limited evidence — not for standalone diagnostic reporting

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
10 Pathogenic / Likely Pathogenic· 128 VUS of 147 total submissions
💊
Clinical Trials
1 active or recruiting trial — 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.
0.24LOEUF
pLI 1.000
Z-score 6.27
OE 0.13 (0.08–0.24)
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.
2.70Z-score
OE missense 0.70 (0.64–0.75)
439 obs / 629.7 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.0.13 (0.08–0.24)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.70 (0.64–0.75)
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: 8 / 60.8Missense obs/exp: 439 / 629.7Syn Z: 1.18

ClinVar Variant Classifications

147 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9
Likely Pathogenic1
VUS128
Likely Benign7
Benign2
9
Pathogenic
1
Likely Pathogenic
128
VUS
7
Likely Benign
2
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
9
0
9
Likely Pathogenic
0
0
1
0
1
VUS
0
118
10
0
128
Likely Benign
0
5
0
2
7
Benign
0
0
0
2
2
Total0123204147

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

View in ClinVar →

Protein Context — Lollipop Plot

RNF40 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
USP14-IMP2-CXCL2 axis in tumor-associated macrophages facilitates resistance to anti-PD-1 therapy in gastric cancer by recruiting myeloid-derived suppressor cells.
You L et al.·Oncogene
2025
The tumor suppressor CDC73 interacts with the ring finger proteins RNF20 and RNF40 and is required for the maintenance of histone 2B monoubiquitination.
Hahn MA et al.·Hum Mol Genet
2012
Loss of RNF40 Decreases NF-κB Activity in Colorectal Cancer Cells and Reduces Colitis Burden in Mice.
Kosinsky RL et al.·J Crohns Colitis
2019
Role of RNF20 in cancer development and progression - a comprehensive review.
Sethi G et al.·Biosci Rep
2018Review
The H2B ubiquitin ligase RNF40 cooperates with SUPT16H to induce dynamic changes in chromatin structure during DNA double-strand break repair.
Kari V et al.·Cell Cycle
2011
RNF20 Links Histone H2B Ubiquitylation with Inflammation and Inflammation-Associated Cancer.
Tarcic O et al.·Cell Rep
2016
Histone H2B monoubiquitination regulates heart development via epigenetic control of cilia motility.
Robson A et al.·Proc Natl Acad Sci U S A
2019
Immunotherapeutic Significance of a Prognostic Alternative Splicing Signature in Bladder Cancer.
Chen J et al.·Technol Cancer Res Treat
2022
RNF20 and histone H2B ubiquitylation exert opposing effects in Basal-Like versus luminal breast cancer.
Tarcic O et al.·Cell Death Differ
2017
Deficiency in mammalian histone H2B ubiquitin ligase Bre1 (Rnf20/Rnf40) leads to replication stress and chromosomal instability.
Chernikova SB et al.·Cancer Res
2012
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Mesothelioma, Malignant Pleural

Genetic Susceptibility in MAlignant Pleural Mesothelioma: Clinical Implication of GermliNE VariaTionS

RECRUITING
NCT06886672Fondazione IRCCS Policlinico San Matteo di PaviaStarted 2023-06-15

External Resources

Links to major genomics databases and tools