GeneBe

RHBDF2

protein-coding

rhomboid 5 homolog 2, the group of Rhomboid family

Gene summary

Predicted to enable protein transporter activity. Predicted to be involved in several processes, including hair follicle morphogenesis; negative regulation of protein secretion; and regulation of signal transduction. Predicted to act upstream of or within protein localization to plasma membrane. Located in plasma membrane. Implicated in palmoplantar keratoderma-esophageal carcinoma syndrome. [provided by Alliance of Genome Resources, Jun 2026]

Previous symbols:
  • RHBDL6
  • TOC

MANE transcript

NM_001005498.4

Inheritance

AD, AR

ClinVar variants

P:2U:291B:123

Top phenotype

Tylosis with esophageal cancer

gnomAD constraint

pLI —, LoF o/e 0.32

Max pathogenic AF

—

Genomic locus

chr17:76,470,891-76,501,790

External References & Databases

Ensembl (ENSG00000129667)NCBI Gene (79651)OMIM (614404)HGNC:20788GenCCUniProt (Q6PJF5)AlphaFoldClinVar (RHBDF2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~30.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

palmoplantar keratoderma-esophageal carcinoma syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007856

Submitter: PanelApp Australia

palmoplantar keratoderma-esophageal carcinoma syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007856

Submitter: Orphanet

palmoplantar keratoderma-esophageal carcinoma syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007856

Submitter: Genomics England PanelApp

palmoplantar keratoderma-esophageal carcinoma syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007856

Submitter: Labcorp Genetics (formerly Invitae)

palmoplantar keratoderma-esophageal carcinoma syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0007856

Submitter: Ambry Genetics

palmoplantar keratoderma-esophageal carcinoma syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0007856

Submitter: Ambry Genetics

palmoplantar keratoderma-esophageal carcinoma syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007856

Submitter: G2P

immunodeficiency diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0021094

Submitter: PanelApp Australia

palmoplantar keratoderma-esophageal carcinoma syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007856

Submitter: ClinGen

Tylosis esophageal cancer (TOC) is an autosomal-dominant (AD) syndrome characterized by palmoplantar keratoderma, oral precursor lesions, and a high lifetime risk of esophageal cancer. The gene-disease relationship of RHBDF2 and TOC was first reported by Blaydon et al. 2012(PMID: 22265016). Five unique missense variants in the RHBDF2 gene were reported to segregate with disease in 6 families, suggesting heterozygous gain of function is the mechanism of tumorigenesis for this gene. This gene-disease relationship is further supported by several mouse models and functional alteration studies. In summary, RHBDF2 is definitively associated with Tylosis esophageal cancer (TOC). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Clinical Genomic Database (CGD)

Tylosis with esophageal cancerAD

Manifestation: Dermatologic; Gastrointestinal; Oncologic

Intervention: Oncologic

Rationale: Surveillance and early detection of and treatment for malignancy may decrease morbidity and mortality; Individuals may be at especially high risk of esophageal cancer with tobacco use

Refs: 13209063; 8508402; 8666405; 8651714; 22265016Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RHBDF2 variants in ClinVar

6 Conditions Cataloged
not providedTotal: 277
Palmoplantar keratoderma-esophageal carcinoma syndromeTotal: 216
Inborn genetic diseasesTotal: 132
not specifiedTotal: 64
RHBDF2-related disorderTotal: 16
HepatoblastomaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001005498.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
10
clinvar
75
clinvar
2
clinvar
 87
missense
2
clinvar
271
clinvar
43
clinvar
3
clinvar
 319
nonsense
3
clinvar
 3
start loss
0
frameshift
4
clinvar
 4
splice donor/acceptor (+/-2bp)
3
clinvar
 3
Total022911185416

Highest pathogenic variant AF is 0.0000020665027

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 75 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001005498.4RefSeqNP_001005498.217MANE Select
ENST00000675367.1EnsemblENSP00000501790.117MANE Select
NM_001376228.1RefSeqNP_001363157.117Standard
NM_001376229.1RefSeqNP_001363158.117Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

  • proteolysis
  • protein transport
  • regulation of epidermal growth factor receptor signaling pathway
  • regulation of protein secretion
  • negative regulation of protein secretion

Molecular Function

  • serine-type endopeptidase activity
  • growth factor binding

Cellular Component

  • endoplasmic reticulum membrane
  • plasma membrane
  • integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000313080
Coding exons
17
Length
30900
Individuals with no LoFs
125714
Homozygous LoFs
0
Heterozygous LoFs
32
Defined
125746
p
0.000127
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.794325500.7850.00003715505
Missense (PolyPhen)148228.830.646762302
Synonymous0.7422152290.9380.00001571674
Loss of Function4.041340.90.3180.00000200430

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000190.00018rare
Latino/Admixed American0.000290.00029rare
Ashkenazi Jewish0.000100.000099rare
East Asian0.0000540.000054rare
Finnish0.000140.00014rare
European (Non-Finnish)0.0000720.000070rare
South Asian0.000160.00016rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Rhomboid protease-like protein which has no protease activity but regulates the secretion of several ligands of the epidermal growth factor receptor. Indirectly activates the epidermal growth factor receptor signaling pathway and may thereby regulate sleep, cell survival, proliferation and migration (By similarity). {ECO:0000250}.;

Recessive Scores

pRec
0.109

Intolerance Scores

LoFtool
0.756
RVIS EVS
-0.37
RVIS percentile EVS
28.29

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.650

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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