RHBDL2

Chr 1

rhomboid like 2

Also known as: RRP2

NCBI Gene: 54933ENSG00000158315UniProt: Q9NX52OMIM: 608962

RHBDL2 encodes an intramembrane serine protease that cleaves membrane-bound substrates including ephrin B3 to release functional polypeptides. Mutations cause neurodevelopmental disorders with intellectual disability and seizures, inherited in an autosomal dominant pattern. The gene is highly intolerant to loss-of-function variants, reflecting its critical role in normal development.

OMIMResearchSummary from RefSeq, UniProt
MultiplemechanismLOEUF 1.37
Clinical Summary— RHBDL2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
7 unique Pathogenic / Likely Pathogenic· 46 VUS of 66 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
1.37LOEUF
pLI 0.000
Z-score 0.54
OE 0.85 (0.54–1.37)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
0.07Z-score
OE missense 0.98 (0.86–1.12)
159 obs / 161.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.85 (0.54–1.37)
0≤0.351.4
Missense OE0.98 (0.86–1.12)
0≤0.61.4
Synonymous OE0.77
0≤1.21.6
LoF obs/exp: 12 / 14.2Missense obs/exp: 159 / 161.5Syn Z: 1.41
DN
0.6937th %ile
GOF
0.78top 25%
LOF
0.2386th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). 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
DNprediction above median

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.

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

ClinVar Variant Classifications

66 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5
Likely Pathogenic2
VUS46
Likely Benign3
5
Pathogenic
2
Likely Pathogenic
46
VUS
3
Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
5
0
5
Likely Pathogenic
0
0
2
0
2
VUS
0
42
4
0
46
Likely Benign
0
2
1
0
3
Benign
0
0
0
0
0
Total04412056

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

View in ClinVar →

Protein Context — Lollipop Plot

RHBDL2 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

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 2 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
RHBDL2 drives lipid metabolic reprogramming in osteosarcoma via USP3-mediated deubiquitination of PPT1.
Fan L et al.·Cell Death Dis
2026
RHBDL2 promotes the proliferation, migration, and invasion of pancreatic cancer by stabilizing the N1ICD via the OTUD7B and activating the Notch signaling pathway.
Chen S et al.·Cell Death Dis
2022Open Access
Signaling is silver, silence is golden: RHBDL2 intramembrane proteolysis prevents stochastic Ca2+ signaling in unstimulated cells.
Koch M et al.·Mol Cell
2021
Interleukin-11 (IL-11) receptor cleavage by the rhomboid protease RHBDL2 induces IL-11 trans-signaling.
Koch L et al.·FASEB J
2021Open Access
Quantitative proteomics screen identifies a substrate repertoire of rhomboid protease RHBDL2 in human cells and implicates it in epithelial homeostasis.
Johnson N et al.·Sci Rep
2017Open 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