RHBDF2

Summary

RHBDF2 (rhomboid 5 homolog 2, HGNC:20788) is a protein-coding gene on chromosome 17q25.1, encoding Inactive rhomboid protein 2 (Q6PJF5). Regulates ADAM17 protease, a sheddase of the epidermal growth factor (EGF) receptor ligands and TNF, thereby plays a role in sleep, cell survival, proliferation, migration and inflammation.

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.

Source: NCBI Gene 79651 — RefSeq curated summary.

At a glance

• Gene–disease (curated): palmoplantar keratoderma-esophageal carcinoma syndrome (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 533 total
• Phenotypes (HPO): 22
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001005498

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20788
Approved symbol	RHBDF2
Name	rhomboid 5 homolog 2
Location	17q25.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ22341, RHBDL5, TOCG, iRhom2
Ensembl gene	ENSG00000129667
Ensembl biotype	protein_coding
OMIM	614404
Entrez	79651

Gene structure

Transcript identifiers

Ensembl transcripts: 35 — 29 protein_coding, 5 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000313080, ENST00000585701, ENST00000585989, ENST00000587640, ENST00000589526, ENST00000589582, ENST00000590168, ENST00000590288, ENST00000590322, ENST00000591192, ENST00000591255, ENST00000591697, ENST00000591860, ENST00000591879, ENST00000591885, ENST00000592123, ENST00000592378, ENST00000593103, ENST00000674875, ENST00000675367, ENST00000878658, ENST00000878660, ENST00000878661, ENST00000878662, ENST00000878663, ENST00000878664, ENST00000878665, ENST00000878666, ENST00000878667, ENST00000878668, ENST00000878669, ENST00000933648, ENST00000933649, ENST00000956560, ENST00000956561

RefSeq mRNA: 5 — MANE Select: NM_001005498 NM_001005498, NM_001376228, NM_001376229, NM_001376230, NM_024599

CCDS: CCDS32743, CCDS32744

Canonical transcript exons

ENST00000675367 — 19 exons

Exon	Start	End
ENSE00001250917	76472686	76472839
ENSE00001250962	76473005	76473105
ENSE00001381363	76487712	76487909
ENSE00002793763	76501353	76501423
ENSE00002798178	76470896	76472052
ENSE00003469504	76474373	76474534
ENSE00003483435	76473648	76473742
ENSE00003486752	76476830	76477024
ENSE00003493329	76473839	76473902
ENSE00003511036	76481375	76481545
ENSE00003537831	76478806	76479009
ENSE00003585715	76475030	76475141
ENSE00003595836	76474033	76474142
ENSE00003616500	76479733	76479854
ENSE00003644559	76473252	76473327
ENSE00003668550	76477657	76477785
ENSE00003680977	76477180	76477298
ENSE00003692901	76474730	76474804
ENSE00003785919	76479082	76479277

Expression profiles

Bgee: expression breadth ubiquitous, 241 present calls, max score 96.65.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.7356 / max 349.5486, expressed in 1724 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
168221	22.4584	1722
168218	0.7578	182
168220	0.5194	229

Top tissues by expression

270 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	96.65	gold quality
monocyte	CL:0000576	94.66	gold quality
mononuclear cell	CL:0000842	94.55	gold quality
leukocyte	CL:0000738	94.40	gold quality
spleen	UBERON:0002106	93.74	gold quality
lower esophagus mucosa	UBERON:0035834	93.72	gold quality
sural nerve	UBERON:0015488	93.00	gold quality
blood	UBERON:0000178	92.36	gold quality
lymph node	UBERON:0000029	91.27	gold quality
skin of leg	UBERON:0001511	90.70	gold quality
skin of abdomen	UBERON:0001416	90.03	gold quality
upper lobe of left lung	UBERON:0008952	89.64	gold quality
esophagus mucosa	UBERON:0002469	89.49	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	89.47	gold quality
upper lobe of lung	UBERON:0008948	89.19	gold quality
vermiform appendix	UBERON:0001154	88.84	gold quality
right lung	UBERON:0002167	88.79	gold quality
bone marrow cell	CL:0002092	88.78	gold quality
tibial nerve	UBERON:0001323	88.09	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.01	gold quality
zone of skin	UBERON:0000014	87.98	gold quality
spinal cord	UBERON:0002240	87.85	gold quality
omental fat pad	UBERON:0010414	87.65	gold quality
peritoneum	UBERON:0002358	87.60	gold quality
tonsil	UBERON:0002372	87.46	gold quality
body of pancreas	UBERON:0001150	87.45	gold quality
caecum	UBERON:0001153	86.91	gold quality
adipose tissue of abdominal region	UBERON:0007808	86.84	gold quality
gingival epithelium	UBERON:0001949	86.78	gold quality
apex of heart	UBERON:0002098	85.50	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	39.18
E-ANND-3	yes	18.58
E-MTAB-9067	yes	13.55
E-MTAB-7606	no	512.34

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CLOCK, MYC, NCOR2

miRNA regulators (miRDB)

25 targeting RHBDF2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-2467-3P	98.65	67.18	1969
HSA-MIR-4490	98.51	68.47	943
HSA-MIR-4436B-3P	98.25	65.26	1494
HSA-MIR-6735-5P	98.24	65.36	1488
HSA-MIR-6834-3P	98.16	65.77	551
HSA-MIR-7843-5P	98.12	65.26	1421
HSA-MIR-4769-3P	97.95	68.17	1002
HSA-MIR-6817-5P	97.95	67.86	1026
HSA-MIR-4632-5P	97.82	65.38	1470
HSA-MIR-6879-5P	97.77	65.52	1521
HSA-MIR-665	97.60	65.64	1781
HSA-MIR-582-3P	96.69	67.38	1019
HSA-MIR-3678-5P	96.64	74.02	93
HSA-MIR-2861	95.24	65.47	1056
HSA-MIR-668-5P	90.24	59.97	79
HSA-MIR-3186-3P	82.87	62.46	32

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 30)

• The distribution of RHBDF2 in tylotic skin is altered in comparison with that in normal skin. (PMID:22265016)
• RHBDF2 and CYGB may play distinctive roles in ovarian cancer and could be added to the growing roster of chromosome 17 genes implicated in this disease. (PMID:22344671)
• Identification of a new missense mutation, p.Asp188Asn, segregating with tylosis with esophageal cancer in a Finnish family, and interestingly the detected mutation alters a codon located between the two previously reported mutation sites. (PMID:22638770)
• Tylosis with oesophageal cancer-associated mutations in iRHOM2 cause an increase in the maturation and activity of ADAM17 in epidermal keratinocytes. (PMID:24643277)
• Our analyses suggest that these DNA methylation changes may have a role in the onset of Alzheimer disease given that we observed them in presymptomatic subjects and that six of the validated genes connect to a known susceptibility gene network. (PMID:25129075)
• results explain how loss of the amino terminus in iRhom1 and iRhom2 impairs TNF signaling, despite enhancing ADAM17 activity (PMID:26535007)
• Study identified iRHOM2 as a novel regulator of K16 in humans and mice, with important implications for palmoplantar keratodermas, wound healing, inflammatory skin disease and cancers. (PMID:28128203)
• The iRhom2 N-terminus stabilizes mature ADAM17 at the cell surface where it cleaves TNF and EGFR in inflammatory and innate immune responses. (Review) (PMID:28815577)
• Uev1A-Ubc13 complex catalyzes lysine63-linked ubiquitination of RHBDF2 to promote TACE maturation. (PMID:29069608)
• In the late phase of RNA viral infection, iRhom2 mediates proteasome-dependent degradation of the E3 ubiquitin ligase MARCH5 and impairs mitochondria-associated degradation (MAD) of VISA. (PMID:29155878)
• iTAP (FRMD8) is a novel iRhom2 interactor that controls TNF-alpha secretion by policing the stability of iRhom2/ADAM17 complex. (PMID:29897333)
• FRMD8 promotes inflammatory and growth factor signaling by stabilizing the iRhom2/ADAM17 sheddase complex. (PMID:29897336)
• The iRhom2 played a key role in the pathogenesis of atherosclerosis, and that iRhom2 might be a potential therapeutic target against atherosclerosis. (PMID:30097271)
• It seems likely that as the involvement of rhomboid 5 homolog 2 protein (iRhom2) IN human diseases is increasingly recognized, they will become the focus of pharmaceutical interest [Review]. (PMID:30890028)
• Results revealed that cervical cancer (CC) tissues had higher levels of iRhom2 than adjacent normal tissues. Its increased expression was significantly associated with tumor stage, size, and parametrium invasion as well as poor outcomes. Cancer stage and iRhom2 expression were independent prognostic indicators of CC. Its knockdown in HeLa cells inhibited cell growth, disrupted the cell cycle, and promoted apoptosis. (PMID:31661139)
• iRhom2 in the pathogenesis of oral squamous cell carcinoma. (PMID:32236893)
• iRhom2 Promotes Hepatic Steatosis by Activating MAP3K7-Dependent Pathway. (PMID:32592194)
• The iRhom2/ADAM17 Axis Attenuates Bacterial Uptake by Phagocytes in a Cell Autonomous Manner. (PMID:32825187)
• The Threshold Effect: Lipopolysaccharide-Induced Inflammatory Responses in Primary Macrophages Are Differentially Regulated in an iRhom2-Dependent Manner. (PMID:33585287)
• Inflammatory activation of surface molecule shedding by upregulation of the pseudoprotease iRhom2 in colon epithelial cells. (PMID:34930929)
• Attenuation of Excess TNF-alpha Release in Crohn’s Disease by Silencing of iRHOMs 1/2 and the Restoration of TGF-beta Mediated Immunosuppression Through Modulation of TACE Trafficking. (PMID:35585977)
• Deficiency in Inactive Rhomboid Protein2 (iRhom2) Alleviates Alcoholic Liver Fibrosis by Suppressing Inflammation and Oxidative Stress. (PMID:35887045)
• iRhom2 regulates ERBB signalling to promote KRAS-driven tumour growth of lung cancer cells. (PMID:35971826)
• The prognostic value of RHBDF2 in Pan-Cancer, and its correlation with cell Adhesion of Hepatocellular Carcinoma. (PMID:36943153)
• RHBDF2 is correlated with immune infiltrates in hepatocellular carcinoma and may have potential as a biomarker. (PMID:36943228)
• EGFR stimulation enables IL-6 trans-signalling via iRhom2-dependent ADAM17 activation in mammary epithelial cells. (PMID:37271223)
• Palmitoyltransferase ZDHHC3 Aggravates Nonalcoholic Steatohepatitis by Targeting S-Palmitoylated IRHOM2. (PMID:37544908)
• Cleavage of the pseudoprotease iRhom2 by the signal peptidase complex reveals an ER-to-nucleus signaling pathway. (PMID:38183983)
• iRhom2 regulates ectodomain shedding and surface expression of the major histocompatibility complex (MHC) class I. (PMID:38570362)
• Cryo-EM reveals that iRhom2 restrains ADAM17 protease activity to control the release of growth factor and inflammatory signals. (PMID:38781971)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
mus_musculus	Rhbdf2	ENSMUSG00000020806
rattus_norvegicus	Rhbdf2	ENSRNOG00000011459
drosophila_melanogaster	rho-5	FBGN0041723
caenorhabditis_elegans		WBGENE00004402
caenorhabditis_elegans		WBGENE00004403

Paralogs (5): RHBDF1 (ENSG00000007384), RHBDL1 (ENSG00000103269), RHBDL3 (ENSG00000141314), RHBDL2 (ENSG00000158315), PARL (ENSG00000175193)

Protein

Protein identifiers

Inactive rhomboid protein 2 — Q6PJF5 (reviewed: Q6PJF5)

Alternative names: Rhomboid 5 homolog 2, Rhomboid family member 2, Rhomboid veinlet-like protein 5, Rhomboid veinlet-like protein 6

All UniProt accessions (11): Q6PJF5, K7EIY3, K7EJ10, K7EJD6, K7EKA3, K7EKI1, K7ELA9, K7EPN8, K7EPV3, K7EQ53, K7EQT5

UniProt curated annotations — full annotation on UniProt →

Function. Regulates ADAM17 protease, a sheddase of the epidermal growth factor (EGF) receptor ligands and TNF, thereby plays a role in sleep, cell survival, proliferation, migration and inflammation. Does not exhibit any protease activity on its own.

Subunit / interactions. Interacts with EGF. Interacts (via cytoplasmic N-terminus) with FRMD8/iTAP; this interaction leads to mutual protein stabilization. Interacts with ADAM17/TACE.

Subcellular location. Endoplasmic reticulum membrane. Cell membrane.

Tissue specificity. Found in the epidermis and esophageal epithelium.

Disease relevance. Tylosis with esophageal cancer (TOC) [MIM:148500] An autosomal dominant syndrome characterized by focal non-epidermolytic palmoplantar keratoderma, oral leukokeratosis, and a high lifetime risk of developing esophageal squamous cell carcinoma. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the peptidase S54 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6PJF5-1	1	yes
Q6PJF5-2	2

RefSeq proteins (5): NP_001005498, NP_001363157, NP_001363158, NP_001363159, NP_078875 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR022241	iRhom1_2_N	Domain
IPR022764	Peptidase_S54_rhomboid_dom	Domain
IPR035952	Rhomboid-like_sf	Homologous_superfamily
IPR051512	Inactive_Rhomboid	Family

Pfam: PF01694, PF12595

UniProt features (79 total): helix 22, strand 14, topological domain 8, transmembrane region 7, sequence variant 7, modified residue 6, turn 5, region of interest 4, sequence conflict 3, chain 1, compositionally biased region 1, splice variant 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
8SNN	ELECTRON MICROSCOPY	2.32
8SNL	ELECTRON MICROSCOPY	2.78
8SNO	ELECTRON MICROSCOPY	2.78
9O58	ELECTRON MICROSCOPY	3.53
8SNM	ELECTRON MICROSCOPY	3.84

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6PJF5-F1	67.53	0.28

Antibody-complex structures (SAbDab): 1 — 9O58

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (6): 90, 113, 117, 323, 325, 328

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9662834	CD163 mediating an anti-inflammatory response

MSigDB gene sets: 268 (showing top): GOBP_REGULATION_OF_INFLAMMATORY_RESPONSE_TO_ANTIGENIC_STIMULUS, GOBP_REGULATION_OF_ERBB_SIGNALING_PATHWAY, GOBP_INFLAMMATORY_RESPONSE, GCANCTGNY_MYOD_Q6, AREB6_03, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_REGULATION_OF_PROTEIN_SECRETION, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_TRANSPORT, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, FOSTER_TOLERANT_MACROPHAGE_UP, GOBP_ERBB_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION, GOBP_NEGATIVE_REGULATION_OF_SECRETION

GO Biological Process (6): negative regulation of inflammatory response to antigenic stimulus (GO:0002862), protein transport (GO:0015031), regulation of epidermal growth factor receptor signaling pathway (GO:0042058), regulation of protein secretion (GO:0050708), negative regulation of protein secretion (GO:0050709), protein localization to plasma membrane (GO:0072659)

GO Molecular Function (4): growth factor binding (GO:0019838), protein transporter activity (GO:0140318), serine-type endopeptidase activity (GO:0004252), protein binding (GO:0005515)

GO Cellular Component (7): endoplasmic reticulum membrane (GO:0005789), Golgi lumen (GO:0005796), plasma membrane (GO:0005886), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), endomembrane system (GO:0012505), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Anti-inflammatory response favouring Leishmania parasite infection	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein secretion	2
inflammatory response to antigenic stimulus	1
regulation of inflammatory response to antigenic stimulus	1
negative regulation of inflammatory response	1
negative regulation of immune response	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
epidermal growth factor receptor signaling pathway	1
regulation of ERBB signaling pathway	1
regulation of protein transport	1
regulation of secretion by cell	1
regulation of protein secretion	1
negative regulation of protein transport	1
negative regulation of secretion by cell	1
protein localization to membrane	1
protein localization to cell periphery	1
protein binding	1
transporter activity	1
endopeptidase activity	1
serine-type peptidase activity	1
binding	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
Golgi apparatus	1
intracellular organelle lumen	1
membrane	1
cell periphery	1
intracellular anatomical structure	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
vacuole	1
plasma membrane	1

Protein interactions and networks

STRING

1146 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RHBDF2	SSR2	P43308	950
RHBDF2	EIF3F	O00303	950
RHBDF2	ADAM17	P78536	931
RHBDF2	CYGB	Q8WWM9	825
RHBDF2	FRMD8	Q9BZ67	821
RHBDF2	RHBDL1	O75783	596
RHBDF2	DIP2A	Q14689	589
RHBDF2	CDH23	Q9H251	543
RHBDF2	RHBDD2	Q6NTF9	490
RHBDF2	KRT16	P08779	485
RHBDF2	PARL	Q9H300	478
RHBDF2	ADAM10	O14672	472
RHBDF2	RHBDD1	Q8TEB9	448
RHBDF2	SERPINF2	P08697	443
RHBDF2	A0A1W2PP11	A0A1W2PP11	441

IntAct

75 interactions, top by confidence:

A	B	Type	Score
ENTREP1	WWP2	psi-mi:“MI:0914”(association)	0.850
GNAI3	RGS12	psi-mi:“MI:0914”(association)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
PDCD1	RTL8C	psi-mi:“MI:0914”(association)	0.530
KCNS3	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
PTGER3	PIK3R2	psi-mi:“MI:0914”(association)	0.530
IL4R	RHOBTB3	psi-mi:“MI:0914”(association)	0.530
HSPB8	VWA8	psi-mi:“MI:0914”(association)	0.530
SLC31A1	C2orf72	psi-mi:“MI:0914”(association)	0.530
EVA1C	STK25	psi-mi:“MI:0914”(association)	0.530
TUBA4A	PLD2	psi-mi:“MI:0914”(association)	0.530
TMEM200A	STX6	psi-mi:“MI:0914”(association)	0.530
CSGALNACT2	TPST1	psi-mi:“MI:0914”(association)	0.530
KCNE3	RIOK3	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
SLITRK3	RHBDF2	psi-mi:“MI:0915”(physical association)	0.400
NS3	C15orf61	psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
	TMEM223	psi-mi:“MI:0914”(association)	0.350
TGFBR2	WWP2	psi-mi:“MI:0914”(association)	0.350
YWHAH	FOXO6	psi-mi:“MI:0914”(association)	0.350
TTMP	TMEM223	psi-mi:“MI:0914”(association)	0.350
BSCL2	TMEM223	psi-mi:“MI:0914”(association)	0.350
S100A2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
S100P	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
NRSN1	FAM171A2	psi-mi:“MI:0914”(association)	0.350
CX3CL1	FAM171A2	psi-mi:“MI:0914”(association)	0.350

BioGRID (212): RHBDF2 (Affinity Capture-MS), RHBDF2 (Affinity Capture-MS), RHBDF2 (Affinity Capture-MS), RHBDF2 (Affinity Capture-MS), RHBDF2 (Affinity Capture-MS), RHBDF2 (Affinity Capture-MS), RHBDF2 (Affinity Capture-MS), RHBDF2 (Affinity Capture-MS), RHBDF2 (Affinity Capture-MS), UBE2V1 (Affinity Capture-Western), RHBDF2 (Affinity Capture-Western), UBE2N (Affinity Capture-Western), STUB1 (Affinity Capture-Western), RHBDF2 (Biochemical Activity), RHBDF2 (Affinity Capture-RNA)

ESM2 similar proteins: A0JPA1, A4GG66, A4GVD1, A4IG66, A7YWH9, A9L8T6, B0VX73, B1MT31, F1NVK6, G5EBQ8, P18861, P28228, P28229, P36383, P91682, Q00M95, Q0IHQ3, Q0P5V9, Q11186, Q16625, Q28269, Q2HJ66, Q3UZP0, Q499S9, Q5BKX6, Q5RFS5, Q5YLM1, Q61146, Q62847, Q66IE4, Q6GMF8, Q6NZH5, Q6P6T5, Q6PIX5, Q6PJF5, Q6PYT3, Q6R4A8, Q6WQJ1, Q7TMB7, Q7ZXS7

Diamond homologs: A0JPA1, A7YWH9, A9L8T6, B0VX73, B1MT31, C8VCL5, F4JBM4, O82756, P54493, Q00M95, Q0WQX7, Q499S9, Q695T8, Q695U0, Q6GMF8, Q6GV23, Q6IUY1, Q6PIX5, Q6PJF5, Q76NQ1, Q80WQ6, Q8VZ48, Q96CC6, Q9CAN1, Q9NX52, Q9SSR0, F4I8K2, P96617, A2AGA4, P46116, Q9LYP1, F4ICF4, P20350, P34356, P58872, P58873, Q84MB5, Q19821, Q9FFX0, Q695T9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

533 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	321
Likely benign	93
Benign	50

Top pathogenic / likely-pathogenic (0)

SpliceAI

2870 predictions. Top by Δscore:

Variant	Effect	Δscore
17:76472680:CCTTA:C	donor_loss	1.0000
17:76472681:CTTA:C	donor_loss	1.0000
17:76472682:TTAC:T	donor_loss	1.0000
17:76472683:TAC:T	donor_loss	1.0000
17:76472684:A:AC	donor_gain	1.0000
17:76472684:A:C	donor_loss	1.0000
17:76472685:C:A	donor_loss	1.0000
17:76472685:C:CC	donor_gain	1.0000
17:76472685:CCT:C	donor_gain	1.0000
17:76472806:T:TC	acceptor_gain	1.0000
17:76472815:C:CT	acceptor_gain	1.0000
17:76472835:CCACG:C	acceptor_gain	1.0000
17:76472836:CACG:C	acceptor_gain	1.0000
17:76472836:CACGC:C	acceptor_gain	1.0000
17:76472837:ACG:A	acceptor_gain	1.0000
17:76472838:CG:C	acceptor_gain	1.0000
17:76472838:CGC:C	acceptor_gain	1.0000
17:76472840:C:CC	acceptor_gain	1.0000
17:76473834:CTCA:C	donor_loss	1.0000
17:76473835:TCAC:T	donor_loss	1.0000
17:76473837:A:AC	donor_gain	1.0000
17:76473837:ACCGG:A	donor_gain	1.0000
17:76473838:C:CC	donor_gain	1.0000
17:76473838:C:CT	donor_loss	1.0000
17:76473838:CCGG:C	donor_gain	1.0000
17:76473838:CCGGC:C	donor_gain	1.0000
17:76474027:CCCTA:C	donor_loss	1.0000
17:76474029:CTACC:C	donor_loss	1.0000
17:76474030:TA:T	donor_loss	1.0000
17:76474031:A:C	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000093165 (17:76497192 C>T), RS1000206677 (17:76501445 C>A,T), RS1000243985 (17:76499767 A>T), RS1000438884 (17:76472393 G>A,T), RS1000458332 (17:76496239 T>C), RS1000520464 (17:76476407 ACTCAGCCT>A), RS1000573419 (17:76500600 G>T), RS1000826580 (17:76471395 T>C), RS1000892782 (17:76486819 C>T), RS1000965719 (17:76491440 G>A,C,T), RS1001096692 (17:76481610 G>A), RS1001201746 (17:76480603 C>T), RS1001206627 (17:76495683 A>G), RS1001241723 (17:76486520 C>G), RS1001289849 (17:76485684 T>C)

Disease associations

OMIM: gene MIM:614404 | disease phenotypes: MIM:148500

GenCC curated gene-disease

Disease	Classification	Inheritance
palmoplantar keratoderma-esophageal carcinoma syndrome	Definitive	Autosomal dominant
immunodeficiency disease	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
palmoplantar keratoderma-esophageal carcinoma syndrome	Definitive	AD

Mondo (3): palmoplantar keratoderma-esophageal carcinoma syndrome (MONDO:0007856), hepatoblastoma (MONDO:0018666), immunodeficiency disease (MONDO:0021094)

Orphanet (2): Palmoplantar keratoderma-esophageal carcinoma syndrome (Orphanet:2198), Hepatoblastoma (Orphanet:449)

HPO phenotypes

22 total (22 of 22 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000982	Palmoplantar keratoderma
HP:0001036	Parakeratosis
HP:0001541	Ascites
HP:0001824	Weight loss
HP:0002015	Dysphagia
HP:0002017	Nausea and vomiting
HP:0002020	Gastroesophageal reflux
HP:0002033	Poor suck
HP:0002239	Gastrointestinal hemorrhage
HP:0002240	Hepatomegaly
HP:0002250	Abnormal large intestine morphology
HP:0002745	Oral leukoplakia
HP:0003621	Juvenile onset
HP:0004396	Poor appetite
HP:0007447	Diffuse palmoplantar hyperkeratosis
HP:0007502	Follicular hyperkeratosis
HP:0011459	Esophageal carcinoma
HP:0025270	Abnormal esophagus physiology
HP:0045026	Abnormal mediastinum morphology
HP:0100751	Esophageal neoplasm
HP:0100760	Clubbing of toes

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST90002381_542	Eosinophil count	2.000000e-10
GCST90002392_27	Mean corpuscular volume	1.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004842	eosinophil count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D018197	Hepatoblastoma	C04.557.435.380
C536164	Keratosis palmoplantaris with esophageal cancer (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs12948783	Efficacy	3	fentanyl;morphine;opioids;oxycodone	Neoplasms

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs12948783	RHBDF2	3	0.00	1	fentanyl;morphine;opioids;oxycodone

CTD chemical–gene interactions

53 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases methylation, increases expression, increases methylation	6
Cyclosporine	decreases expression, increases expression	3
Estradiol	increases expression	2
Tretinoin	decreases expression, increases expression	2
Aflatoxin B1	affects expression, increases expression	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
methyleugenol	increases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
tris(2-butoxyethyl) phosphate	affects expression	1
sulforaphane	increases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
manganese chloride	increases abundance, increases expression	1
benzo(e)pyrene	decreases methylation	1
coumarin	decreases phosphorylation	1
beta-methylcholine	affects expression	1
perfluoro-n-nonanoic acid	increases expression	1
2-palmitoylglycerol	increases expression	1
jinfukang	increases expression, affects cotreatment	1
Sunitinib	increases expression	1
Zoledronic Acid	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Atrazine	increases expression	1
Caffeine	affects phosphorylation	1
Cisplatin	affects cotreatment, increases expression	1
Copper	affects binding, increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

303 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00001542	PHASE4	COMPLETED	Fluconazole Prophylaxis of Thrush in AIDS
NCT00144157	PHASE4	COMPLETED	Open Label Study of NVP+CBV Treatment in Women Who Have Received sdNVP for the pMTCT of HIV
NCT00162643	PHASE4	UNKNOWN	PI Vs. NNRTI Based Therapy for HIV Advanced Disease
NCT00273988	PHASE4	COMPLETED	Pharmacokinetic Study of Interaction Between Nevirapine and Methadone in HIV-1 Infected, Opioid-dependent Adults
NCT00981318	PHASE4	TERMINATED	Pilot Assessment of Lopinavir/Ritonavir and Maraviroc
NCT01086878	PHASE4	COMPLETED	Safety of Cotrimoxazole in HIV- and HAART-exposed Infants
NCT01090102	PHASE4	COMPLETED	Mesalamine to Reduce T Cell Activation in HIV Infection
NCT01147042	PHASE4	TERMINATED	Biochemical Response to Interferon-Gamma in Subjects With Specific Gene Mutation in Chronic Granulomatous Disease
NCT01230580	PHASE4	UNKNOWN	Protease Inhibitor Monotherapy Versus Ongoing Triple-therapy in the Long Term Management of HIV Infection (PIVOT)
NCT01465958	PHASE4	COMPLETED	Pharmacokinetics, Safety, and Tolerability of Subcutaneous GAMUNEX-C in Pediatric Subjects With Primary Immunodeficiency
NCT02274662	PHASE4	COMPLETED	Expanded Access Protocol Thymus Transplantation
NCT02348177	PHASE4	COMPLETED	Pharmacokinetics of Lopinavir/Ritonavir Superboosting in Infants and Young Children Co-infected With HIV and TB
NCT02396979	PHASE4	COMPLETED	Intervention of HIV, Drug Use and the Criminal Justice System in Malaysia
NCT02490956	PHASE4	UNKNOWN	Diagnostic Immunization With Rabies Vaccine in Patients With PID
NCT02503293	PHASE4	COMPLETED	A Study to Compare Quality of Life and Satisfaction in Primary Immunodeficient Patients Treated With Subcutaneous Injections of Gammanorm® 165 mg/mL Administered With Two Different Delivery Devices: Injections Using Pump or Rapid Push
NCT02881437	PHASE4	COMPLETED	IgG Level in Primary Immunodeficiency Switching From Standard SCIG to Every Other Week HyQvia
NCT03033745	PHASE4	COMPLETED	Safety and Tolerability of Higher Infusion Parameters of IgPro20 (Hizentra) in Subjects With Primary Immunodeficiency (PID)
NCT03677557	PHASE4	UNKNOWN	Safety, Tolerability, Patient Satisfaction and Cost of 16.5% Subcutaneous Immunoglobulin (Cutaquig®) Treatment
NCT04192487	PHASE4	COMPLETED	Effects of Crofelemer on the Gut Microbiome in Healthy Volunteers and in HIV+ Patients With Non-Infectious Diarrhea
NCT04566692	PHASE4	COMPLETED	A Study to Evaluate IGSC 20% Biweekly Dosing in Treatment-Experienced Participants and Loading/Maintenance Dosing in Treatment-Naïve Participants With Primary Immunodeficiency
NCT05493969	PHASE4	NOT_YET_RECRUITING	Efficacy and Tolerability of DTG Plus 3TC in HIV Infected Adults With Virologically Suppression and TDF Toxicity
NCT06576024	PHASE4	COMPLETED	Immunogenicity and Safety of Inactivated Hepatitis A Vaccine in HIV-infected People
NCT06634641	PHASE4	RECRUITING	Clozapine-related Immunodeficiency in Parkinsons Disease
NCT07076446	PHASE4	ACTIVE_NOT_RECRUITING	An Open-label, Multicenter Study to Assess the Pharmacokinetics (PK), Safety, and Tolerability of Subcutaneous IgPro20 in Immunoglobulin (IG) Treatment-naïve Participants With Primary Immunodeficiency (PID)
NCT02933333	PHASE4	UNKNOWN	G-CSF Alone or Combination With GM-CSF on Prevention and Treatment of Infection in Children With Malignant Tumor
NCT00000118	PHASE3	COMPLETED	Ganciclovir Implant Study for Cytomegalovirus Retinitis
NCT00000134	PHASE3	COMPLETED	Studies of the Ocular Complications of AIDS (SOCA)–Cytomegalovirus Retinitis Retreatment Trial (CRRT)
NCT00000590	PHASE3	COMPLETED	Anti-HIV Immunoglobulin (HIVIG) in Prevention of Maternal-Fetal HIV Transmission (Pediatric ACTG Protocol 185)
NCT00001267	PHASE3	COMPLETED	A Randomized Pilot Study for the Treatment of AIDS or AIDS Related Complex With an Alternating or Simultaneous Combination Regimen of AZT and 2’,3’-Dideoxyinosine
NCT00001646	PHASE3	COMPLETED	Voriconazole vs. Amphotericin B in the Treatment of Invasive Aspergillosis
NCT00144183	PHASE3	COMPLETED	A Study of Single Dose Nevirapine (NVP) Combined With Combivir® for the Prevention of Mother to Child Transmission (pMTCT) - Treatment Options Preservation Study (TOPS)
NCT00243568	PHASE3	WITHDRAWN	Vicriviroc, a CCR5 Inhibitor, Added to an Optimized Antiretroviral Therapy for Previously Treated HIV (VICTOR-E2) (Study P04285
NCT00278954	PHASE3	COMPLETED	Efficacy, Safety and Pharmacokinetics of Gammaplex in Primary Immunodeficiency Diseases.
NCT00474370	PHASE3	COMPLETED	Vicriviroc in HIV-Treatment Experienced Subjects (Study P04889AM8)(COMPLETED)
NCT00478231	PHASE3	COMPLETED	Multicenter, Safety Study Of Maraviroc
NCT00523211	PHASE3	COMPLETED	Vicriviroc in HIV-Treatment Experienced Subjects (Study P04405AM5)
NCT00698334	PHASE3	COMPLETED	Efficacy of Thrice Weekly Directly Observed Treatment, Short-course (DOTS) in HIV-associated Tuberculosis
NCT00966160	PHASE3	COMPLETED	CD4 Cell Recovery in HIV-1 Patients Comparing 2 Treatment Regimes
NCT01363011	PHASE3	COMPLETED	Cobicistat-containing Highly Active Antiretroviral Regimens in HIV-1 Infected Patients With Mild to Moderate Renal Impairment
NCT01440569	PHASE3	COMPLETED	Safety and Efficacy of Cobicistat-boosted Darunavir in HIV Infected Adults