RNF40

Chr 16

ring finger protein 40

Also known as: BRE1B, RBP95, STARING

NCBI Gene: 9810ENSG00000103549UniProt: O75150

RNF40 encodes an E3 ubiquitin ligase that forms a complex with RNF20 to monoubiquitinate histone H2B, which is essential for transcriptional activation and proper histone methylation patterns. Mutations cause an autosomal dominant neurodevelopmental disorder with intellectual disability, developmental delay, and distinctive facial features. This gene is highly constrained against loss-of-function variants, reflecting its critical role in epigenetic regulation.

ResearchSummary from RefSeq, UniProt
LOFmechanismLOEUF 0.24
Clinical Summary— RNF40
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Gene-Disease Validity (ClinGen)
congenital heart disease · ADLimited

Limited evidence — not for standalone diagnostic reporting

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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.
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ClinVar Variants
10 unique Pathogenic / Likely Pathogenic· 128 VUS of 165 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
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
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
LoF OE0.13 (0.08–0.24)
0≤0.351.4
Missense OE0.70 (0.64–0.75)
0≤0.61.4
Synonymous OE0.90
0≤1.21.6
LoF obs/exp: 8 / 60.8Missense obs/exp: 439 / 629.7Syn Z: 1.18
DN
0.5280th %ile
GOF
0.4184th %ile
LOF
0.67top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.24

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

165 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.

3D Protein StructureAlphaFold
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
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