RNF135

Chr 17

ring finger protein 135

Also known as: L13, MMFD, REUL, Riplet

NCBI Gene: 84282ENSG00000181481UniProt: Q8IUD6

The protein encoded by this gene contains a RING finger domain, a motif present in a variety of functionally distinct proteins and known to be involved in protein-protein and protein-DNA interactions. This gene is located in a chromosomal region known to be frequently deleted in patients with neurofibromatosis. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

1
Active trials
50
Pathogenic / LP
196
ClinVar variants
4
Pubs (1 yr)
0.1
Missense Z
1.44
LOEUF
Clinical Summary— RNF135
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
50 Pathogenic / Likely Pathogenic· 102 VUS of 196 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
Tolerant — LoF & missense variants common in population
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.
1.44LOEUF
pLI 0.000
Z-score 0.28
OE 0.92 (0.61–1.44)
Tolerant

Highly tolerant — LoF variants common in population

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.
0.09Z-score
OE missense 0.98 (0.88–1.10)
215 obs / 218.6 exp
Tolerant

Mild missense constraint

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.0.92 (0.61–1.44)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.98 (0.88–1.10)
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.1.05
0≤1.21.6
LoF obs/exp: 14 / 15.2Missense obs/exp: 215 / 218.6Syn Z: -0.36

ClinVar Variant Classifications

196 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic45
Likely Pathogenic5
VUS102
Likely Benign31
Benign12
Conflicting1
45
Pathogenic
5
Likely Pathogenic
102
VUS
31
Likely Benign
12
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
44
0
45
Likely Pathogenic
0
0
5
0
5
VUS
5
75
21
1
102
Likely Benign
0
11
11
9
31
Benign
0
4
6
2
12
Conflicting
—1
Total6908712196

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

View in ClinVar →

Protein Context — Lollipop Plot

RNF135 · protein map & ClinVar variants

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

Gene2Phenotype Curations

RNF135-related macrocephaly, macrosomia, facial dysmorphism syndrome

limited
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Assessing the Pathogenicity, Penetrance, and Expressivity of Putative Disease-Causing Variants in a Population Setting.
Wright CF et al.·Am J Hum Genet
2019
Clinical-Genetic Approach to Conditions with Macrocephaly and ASD/Behaviour Abnormalities: Variants in PTEN and PPP2R5D Are the Most Recurrent Gene Mutations in a Patient-Oriented Diagnostic Strategy.
L'Erario FF et al.·Genes (Basel)
2025
A pan-cancer analysis of ring finger protein 135 and its relationship to triple-negative breast cancer proliferation and metastasis.
Yao Y et al.·Aging (Albany NY)
2022
Mutation screening of the ubiquitin ligase gene RNF135 in French patients with autism.
Tastet J et al.·Psychiatr Genet
2015Cohort
Clinical and molecular characterization of neurofibromatosis in southern Brazil.
Rosset C et al.·Expert Rev Mol Diagn
2018Clinical trial
Identification of an atypical microdeletion generating the RNF135-SUZ12 chimeric gene and causing a position effect in an NF1 patient with overgrowth.
Ferrari L et al.·Hum Genet
2017
Deregulated expression of polycomb repressive complex 2 target genes in a NF1 patient with microdeletion generating the RNF135-SUZ12 chimeric gene.
Tritto V et al.·Neurogenetics
2023
The Role of Co-Deleted Genes in Neurofibromatosis Type 1 Microdeletions: An Evolutive Approach.
Brussa Reis L et al.·Genes (Basel)
2019
Mutations in RNF135, a gene within the NF1 microdeletion region, cause phenotypic abnormalities including overgrowth.
Douglas J et al.·Nat Genet
2007
Single-Cell Data and Weighted Correlation Network Analysis Revealed the Regulatory Mechanisms of Macrophages in Carotid Plaques.
Ding Y et al.·J Immunol Res
2025Functional
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 4 full-text resultsSearch PubTator3 ↗

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