RHBDF2

Chr 17AD

rhomboid 5 homolog 2

Also known as: RHBDL5, RHBDL6, TOC, TOCG, iRhom2

NCBI Gene: 79651ENSG00000129667UniProt: Q6PJF5

Predicted to enable protein transporter activity. Predicted to be involved in negative regulation of protein secretion and regulation of epidermal growth factor receptor signaling pathway. Predicted to act upstream of or within protein localization to plasma membrane and regulation of metalloendopeptidase activity. Located in plasma membrane. Implicated in palmoplantar keratoderma-esophageal carcinoma syndrome. [provided by Alliance of Genome Resources, Apr 2025]

Primary Disease Associations & Inheritance

Tylosis with esophageal cancerMIM #148500
AD
534
ClinVar variants
14
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— RHBDF2
🧬
Gene-Disease Validity (ClinGen)
palmoplantar keratoderma-esophageal carcinoma syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.
📋
ClinVar Variants
14 Pathogenic / Likely Pathogenic· 323 VUS of 534 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.51LOEUF
pLI 0.001
Z-score 4.04
OE 0.32 (0.21–0.51)
Moderately constrained

More LoF-intolerant than ~75% 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.
1.79Z-score
OE missense 0.78 (0.72–0.85)
432 obs / 550.3 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.0.32 (0.21–0.51)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.78 (0.72–0.85)
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.0.94
0≤1.21.6
LoF obs/exp: 13 / 40.9Missense obs/exp: 432 / 550.3Syn Z: 0.74

ClinVar Variant Classifications

534 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12
Likely Pathogenic2
VUS323
Likely Benign116
Benign51
Conflicting30
12
Pathogenic
2
Likely Pathogenic
323
VUS
116
Likely Benign
51
Benign
30
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
12
0
12
Likely Pathogenic
0
1
1
0
2
VUS
5
267
43
8
323
Likely Benign
0
12
40
64
116
Benign
0
5
40
6
51
Conflicting
—30
Total528513678534

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

View in ClinVar →

Protein Context — Lollipop Plot

RHBDF2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

RHBDF2-related tylosis with esophageal cancer

definitive
ADGain Of FunctionAltered Gene Product Structure
SkinCancer
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Tylosis with esophageal cancer

MIM #148500

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Congenital iRHOM2 deficiency causes ADAM17 dysfunction and environmentally directed immunodysregulatory disease.
Kubo S et al.·Nat Immunol
2022Clinical trial
A Feedback Loop Between Fatty Acid Metabolism and Epigenetics in Clear Cell Renal Carcinoma.
Ye Z et al.·Adv Sci (Weinh)
2025
The E3 ubiquitin-protein ligase Trim31 alleviates non-alcoholic fatty liver disease by targeting Rhbdf2 in mouse hepatocytes.
Xu M et al.·Nat Commun
2022Functional
Tylosis with oesophageal cancer: Diagnosis, management and molecular mechanisms.
Ellis A et al.·Orphanet J Rare Dis
2015Review
iRHOM2 is a critical pathogenic mediator of inflammatory arthritis.
Issuree PD et al.·J Clin Invest
2013
[Genetics of complex and syndromic palmoplantar keratoderma].
Sperelakis-Beedham B et al.·Ann Biol Clin (Paris)
2021Review
Identification of novel candidate predisposing genes in familial nonmedullary thyroid carcinoma implicating DNA damage repair pathways.
Pires C et al.·Int J Cancer
2025
Candidate susceptibility variants for esophageal squamous cell carcinoma.
Donner I et al.·Genes Chromosomes Cancer
2017
Free-flow zone electrophoresis facilitated proteomics analysis of heterogeneous subpopulations in H1299 lung cancer cells.
Sohail A et al.·Anal Chim Acta
2022
Opioid treatment failure in cancer patients: the role of clinical and genetic factors.
Oosten AW et al.·Pharmacogenomics
2016Cohort
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools