RNF40

Chr 16

ring finger protein 40

Also known as: BRE1B, RBP95, STARING

NCBI Gene: 9810 ENSG00000103549 UniProt: 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

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]

ResearchGenerating clinical summary…

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

118 VUS of 145 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 OE?0.13 (0.08–0.24)

0≤0.351.4

Missense OE?0.70 (0.64–0.75)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 8 / 60.8Missense obs/exp: 439 / 629.7Syn Z: 1.18

This gene — mechanism propensity

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

145 submitted variants in ClinVar

ClinVar

Classification Summary

VUS118

Likely Benign7

Benign2

118

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	118	0	118
Likely Benign	5	2	7
Benign	0	2	2
Total	123	4	127

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

View in ClinVar →

10 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap RNF40 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →