RHBDD1

Summary

RHBDD1 (rhomboid domain containing 1, HGNC:23081) is a protein-coding gene on chromosome 2q36.3, encoding Rhomboid-related protein 4 (Q8TEB9). Intramembrane-cleaving serine protease that cleaves single transmembrane or multi-pass membrane proteins in the hydrophobic plane of the membrane, luminal loops and juxtamembrane regions.

Enables serine-type endopeptidase activity. Involved in several processes, including cellular response to unfolded protein; membrane protein proteolysis; and positive regulation of protein catabolic process. Located in endoplasmic reticulum.

Source: NCBI Gene 84236 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 61 total — 1 pathogenic
• MANE Select transcript: NM_001167608

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23081
Approved symbol	RHBDD1
Name	rhomboid domain containing 1
Location	2q36.3
Locus type	gene with protein product
Status	Approved
Aliases	DKFZp547E052, RHBDL4
Ensembl gene	ENSG00000144468
Ensembl biotype	protein_coding
OMIM	617515
Entrez	84236

Gene structure

Transcript identifiers

Ensembl transcripts: 42 — 36 protein_coding, 4 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000341329, ENST00000392062, ENST00000409053, ENST00000423616, ENST00000424132, ENST00000436481, ENST00000437454, ENST00000443477, ENST00000448992, ENST00000450679, ENST00000473218, ENST00000483268, ENST00000491490, ENST00000493526, ENST00000539613, ENST00000882925, ENST00000882926, ENST00000882927, ENST00000882928, ENST00000882929, ENST00000882930, ENST00000882931, ENST00000882932, ENST00000882933, ENST00000882934, ENST00000882935, ENST00000882936, ENST00000882937, ENST00000882938, ENST00000882939, ENST00000882940, ENST00000882941, ENST00000882942, ENST00000882943, ENST00000928315, ENST00000928316, ENST00000928317, ENST00000928318, ENST00000944649, ENST00000944650, ENST00000944651, ENST00000944652

RefSeq mRNA: 5 — MANE Select: NM_001167608 NM_001167608, NM_001349069, NM_001349071, NM_001349072, NM_032276

CCDS: CCDS2464

Canonical transcript exons

ENST00000392062 — 9 exons

Exon	Start	End
ENSE00001510565	226995431	226999210
ENSE00001632102	226839409	226839627
ENSE00001738720	226838073	226838154
ENSE00002248117	226836054	226836087
ENSE00003479869	226914208	226914351
ENSE00003517328	226908822	226908878
ENSE00003889058	226906793	226906881
ENSE00003893968	226864604	226865126
ENSE00003894893	226867186	226867318

Expression profiles

Bgee: expression breadth ubiquitous, 248 present calls, max score 95.22.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.8865 / max 155.8396, expressed in 1798 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
25705	14.5751	1798
25713	0.1108	28
25712	0.0979	22
25706	0.0682	31
25711	0.0076	6
25715	0.0067	1
25708	0.0058	1
25709	0.0058	3
25710	0.0045	2
25707	0.0040	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bone marrow cell	CL:0002092	95.22	gold quality
calcaneal tendon	UBERON:0003701	92.81	gold quality
secondary oocyte	CL:0000655	92.08	gold quality
oocyte	CL:0000023	91.84	gold quality
adrenal tissue	UBERON:0018303	91.60	gold quality
thymus	UBERON:0002370	91.01	gold quality
left ventricle myocardium	UBERON:0006566	89.70	silver quality
islet of Langerhans	UBERON:0000006	89.48	gold quality
cardiac muscle of right atrium	UBERON:0003379	89.40	silver quality
monocyte	CL:0000576	88.99	gold quality
leukocyte	CL:0000738	88.78	gold quality
stromal cell of endometrium	CL:0002255	88.75	gold quality
smooth muscle tissue	UBERON:0001135	88.66	gold quality
colonic epithelium	UBERON:0000397	88.46	gold quality
corpus callosum	UBERON:0002336	88.37	gold quality
vermiform appendix	UBERON:0001154	87.26	gold quality
gall bladder	UBERON:0002110	87.23	gold quality
oviduct epithelium	UBERON:0004804	87.18	gold quality
tendon	UBERON:0000043	86.91	gold quality
lymph node	UBERON:0000029	86.53	gold quality
sperm	CL:0000019	86.27	gold quality
rectum	UBERON:0001052	85.88	gold quality
tonsil	UBERON:0002372	85.72	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.51	gold quality
fallopian tube	UBERON:0003889	85.28	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.23	gold quality
caecum	UBERON:0001153	84.71	gold quality
pancreas	UBERON:0001264	84.66	gold quality
endothelial cell	CL:0000115	84.55	gold quality
urinary bladder	UBERON:0001255	84.17	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	15.74

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

150 targeting RHBDD1, 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-3163	100.00	77.23	8605
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509

Literature-anchored findings (GeneRIF, showing 23)

• RHBDD1, a serine protease, modulates BIK-mediated apoptotic activity. (PMID:18953687)
• RHBDD1 is involved in the regulation of a nonclassical exosomal secretion pathway through the restriction of TSAP6. (PMID:22624035)
• Our data show that in vitro RHBDD1 silencing regulates HepG2 cell proliferation and apoptosis. (PMID:23534782)
• RHBDD1 could inhibit cell apoptosis by activating and upregulating c-Jun and its downstream target, Bcl-3 (PMID:23669365)
• this study shows that RHBDD1 gene engineering could be used as an effective tool in malignant brain tumor therapy. (PMID:23883433)
• RHBDL4-mediated APP processing provides insight into APP and rhomboid physiology and qualifies for further investigations to elaborate its impact on Alzheimer disease pathology. (PMID:27563067)
• Tissue microarray assays demonstrated a correlation between RHBDD1 and EGFR in colorectal cancer patients. Therefore, our findings indicate that RHBDD1 stimulates EGFR expression by promoting the AP-1 pathway. (PMID:28445956)
• we proved that RHBDD1 can promote CRC metastasis through the Wnt signaling pathway and ZEB1. As a membrane protein, RHBDD1 has the potential and advantage to become a new therapeutic target or clinical biomarker for metastatic CRC. (PMID:29426364)
• The activity of RHBDL4 is regulated by cholesterol likely through a direct binding of cholesterol to the enzyme. (PMID:30143535)
• RHBDD1 promotes breast cancer progression by regulating p-Akt and CDK2 protein levels (PMID:30286765)
• Bioinformatics analyses revealed that BioID hits of RHBDL4 overlap with factors related to protein stress at the ER, including proteins that interact with p97/VCP. PTP1B (protein-tyrosine phosphatase nonreceptor type 1, also called PTPN1) was also identified as a potential proximity factor and interactor of RHBDL4 (PMID:31177093)
• RHBDD1 is a direct target of miR-138-5p. MiR-138-5p directly binds to the 3’-UTR of the RHBDD1 transcript to inhibit the expression of RHBDD1 in breast cancer cells. RHBDD1 and miR-138-5p appear to play an opposite role in breast cancer cell migration and invasion. (PMID:31243644)
• miR-145-5p was inversely related with RHBDD1 expression in CRC tissues. miR-145-5p was found to directly bind to RHBDD1 and restrained its expression in CRC cells. miR-145-5p overexpression repressed CRC cell proliferation, invasion, migration and induced apoptosis, and these effects were reversed by RHBDD1 upregulation. (PMID:31693935)
• RHBDD1 promotes proliferation, migration, invasion and EMT in renal cell carcinoma via the EGFR/AKT signaling pathway. (PMID:34581421)
• Rhomboid domain containing 1 promotes the growth of non-small cell lung cancer through the activation of EGFR and regulation of the BIK-mediated apoptosis. (PMID:34962825)
• Suppression of rhomboid domain-containing 1 produces anticancer effects in pancreatic adenocarcinoma through affection of the AKT/GSK-3beta/beta-catenin pathway. (PMID:35442567)
• Prognostic and Immunological Significance of Rhomboid Domain Containing Protein 1 in Multiple Primary Cancers. (PMID:35692140)
• MiR-5195-3p functions as a tumor suppressor by targeting RHBDD1 in ovarian cancer. (PMID:36825753)
• Putative Protein Interactome of the Rhomboid Protease RHBDL4. (PMID:36857408)
• RHBDD1 Promotes the Growth and Stemness Characteristics of Gastric Cancer Cells by Activating Wnt/beta-catenin Signaling Pathway. (PMID:37861049)
• RHBDL4-triggered downregulation of COPII adaptor protein TMED7 suppresses TLR4-mediated inflammatory signaling. (PMID:38453906)
• Eta-secretase-like processing of the amyloid precursor protein (APP) by the rhomboid protease RHBDL4. (PMID:38992438)
• CircRHBDD1 promotes immune escape via IGF2BP2/PD-L1 signaling and acts as a nanotherapeutic target in gastric cancer. (PMID:39080693)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	rhbdd1	ENSDARG00000021046
mus_musculus	Rhbdd1	ENSMUSG00000026142
rattus_norvegicus	Rhbdd1	ENSRNOG00000054963

Paralogs (2): RHBDD2 (ENSG00000005486), RHBDD3 (ENSG00000100263)

Protein

Protein identifiers

Rhomboid-related protein 4 — Q8TEB9 (reviewed: Q8TEB9)

Alternative names: Rhomboid domain-containing protein 1, Rhomboid-like protein 4

All UniProt accessions (7): Q8TEB9, B9A054, C9J1R4, C9J4C7, C9JAS2, C9JQK8, C9K011

UniProt curated annotations — full annotation on UniProt →

Function. Intramembrane-cleaving serine protease that cleaves single transmembrane or multi-pass membrane proteins in the hydrophobic plane of the membrane, luminal loops and juxtamembrane regions. Involved in regulated intramembrane proteolysis and the subsequent release of functional polypeptides from their membrane anchors. Functional component of endoplasmic reticulum-associated degradation (ERAD) for misfolded membrane proteins. Required for the degradation process of some specific misfolded endoplasmic reticulum (ER) luminal proteins. Participates in the transfer of misfolded proteins from the ER to the cytosol, where they are destroyed by the proteasome in a ubiquitin-dependent manner. Functions in BIK, MPZ, PKD1, PTCRA, RHO, STEAP3 and TRAC processing. Involved in the regulation of exosomal secretion; inhibits the TSAP6-mediated secretion pathway. Involved in the regulation of apoptosis; modulates BIK-mediated apoptotic activity. Also plays a role in the regulation of spermatogenesis; inhibits apoptotic activity in spermatogonia.

Subunit / interactions. Interacts (via C-terminal domain) with VCP. Interacts with ubiquitin and ubiquitinated proteins. Interacts with BIK and STEAP3.

Subcellular location. Endoplasmic reticulum membrane. Mitochondrion membrane.

Tissue specificity. Expressed strongly in testis.

Activity regulation. Inhibited by aprotinin.

Induction. Up-regulated by endoplasmic reticulum stress agents that induce the unfolded protein response (UPR).

Similarity. Belongs to the peptidase S54 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8TEB9-1	1	yes
Q8TEB9-2	2

RefSeq proteins (5): NP_001161080, NP_001335998, NP_001336000, NP_001336001, NP_115652 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR022764	Peptidase_S54_rhomboid_dom	Domain
IPR035952	Rhomboid-like_sf	Homologous_superfamily

Pfam: PF01694

Enzyme classification (BRENDA):

• EC 3.4.21.105 — rhomboid protease (BRENDA: 42 organisms, 229 substrates, 68 inhibitors, 19 Km, 19 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
BODIPY FL CASEIN	0.0007–0.0029	12
FL-CASEIN	0.0018–0.0065	3
TATA	0.0076–0.119	3
CYPET-TATA-YPET	0.0039	1

UniProt features (23 total): topological domain 5, transmembrane region 4, region of interest 3, active site 2, splice variant 2, mutagenesis site 2, chain 1, compositionally biased region 1, sequence variant 1, sequence conflict 1, helix 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
5EPP	X-RAY DIFFRACTION	1.88

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TEB9-F1	78.80	0.49

Functional residue map

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

Catalytic / active sites (2): 144 (nucleophile); 195

Mutagenesis-validated functional residues (2):

Position	Phenotype
142	enzyme inactivation. reduces the cleavage of bik.
144	enzyme inactivation. reduces the cleavage of bik and tsap6. increases tsap6-mediated exosome secretion.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 151 (showing top): GOBP_POSITIVE_REGULATION_OF_PROTEIN_MATURATION, GOBP_ENDOPLASMIC_RETICULUM_TO_CYTOSOL_TRANSPORT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_CELLULAR_RESPONSE_TO_UV, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_CELLULAR_RESPONSE_TO_LIGHT_STIMULUS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_MALE_GAMETE_GENERATION, GOBP_CELLULAR_RESPONSE_TO_TOPOLOGICALLY_INCORRECT_PROTEIN, GOBP_PROTEIN_MATURATION, GOBP_REGULATION_OF_CATABOLIC_PROCESS

GO Biological Process (17): apoptotic process (GO:0006915), positive regulation of protein processing (GO:0010954), membrane protein intracellular domain proteolysis (GO:0031293), membrane protein proteolysis (GO:0033619), cellular response to unfolded protein (GO:0034620), cellular response to UV (GO:0034644), ERAD pathway (GO:0036503), negative regulation of apoptotic process (GO:0043066), post-translational protein modification (GO:0043687), positive regulation of protein catabolic process (GO:0045732), spermatid differentiation (GO:0048515), positive regulation of secretion (GO:0051047), membrane protein proteolysis involved in retrograde protein transport, ER to cytosol (GO:1904211), proteolysis (GO:0006508), spermatogenesis (GO:0007283), cell differentiation (GO:0030154), positive regulation of protein metabolic process (GO:0051247)

GO Molecular Function (6): endopeptidase activity (GO:0004175), serine-type endopeptidase activity (GO:0004252), protein binding (GO:0005515), peptidase activity (GO:0008233), serine-type peptidase activity (GO:0008236), hydrolase activity (GO:0016787)

GO Cellular Component (6): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), mitochondrial membrane (GO:0031966), endoplasmic reticulum quality control compartment (GO:0044322), mitochondrion (GO:0005739), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
membrane protein proteolysis	2
developmental process involved in reproduction	2
protein metabolic process	2
peptidase activity	2
cytoplasm	2
intracellular membrane-bounded organelle	2
organelle membrane	2
cellular anatomical structure	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
protein processing	1
positive regulation of proteolysis	1
regulation of protein processing	1
positive regulation of protein maturation	1
proteolysis	1
response to unfolded protein	1
cellular response to topologically incorrect protein	1
response to UV	1
cellular response to light stimulus	1
proteasomal protein catabolic process	1
response to endoplasmic reticulum stress	1
response to chemical	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
protein modification process	1
positive regulation of catabolic process	1
protein catabolic process	1
regulation of protein catabolic process	1
positive regulation of protein metabolic process	1
spermatogenesis	1
cellular process involved in reproduction in multicellular organism	1
cell differentiation	1
secretion	1
regulation of secretion	1
positive regulation of transport	1
retrograde protein transport, ER to cytosol	1
male gamete generation	1
cellular developmental process	1

Protein interactions and networks

STRING

1016 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RHBDD1	RHBDL1	O75783	724
RHBDD1	RHBDD2	Q6NTF9	634
RHBDD1	RHBDL3	P58872	602
RHBDD1	RHBDL2	Q9NX52	570
RHBDD1	RHBDF1	Q96CC6	541
RHBDD1	COL4A4	P53420	526
RHBDD1	PARL	Q9H300	499
RHBDD1	RHBDD3	Q9Y3P4	490
RHBDD1	TMEM214	Q6NUQ4	479
RHBDD1	A0A1W2PP11	A0A1W2PP11	463
RHBDD1	EGFR	P00533	450
RHBDD1	RHBDF2	Q6PJF5	448
RHBDD1	POPDC2	Q9HBU9	446
RHBDD1	TMEM38A	Q9H6F2	443
RHBDD1	BIK	Q13323	435

IntAct

109 interactions, top by confidence:

A	B	Type	Score
ENTREP1	WWP2	psi-mi:“MI:0914”(association)	0.850
RHBDD1	RNF5	psi-mi:“MI:0915”(physical association)	0.670
LPCAT2	RHBDD1	psi-mi:“MI:0915”(physical association)	0.560
RHBDD1	CREB3L1	psi-mi:“MI:0915”(physical association)	0.560
RHBDD1	PLEKHB2	psi-mi:“MI:0915”(physical association)	0.560
PPGB	RHBDD1	psi-mi:“MI:0915”(physical association)	0.560
GYPC	RHBDD1	psi-mi:“MI:0915”(physical association)	0.560
	RHBDD1	psi-mi:“MI:0915”(physical association)	0.560
SEC22B	RHBDD1	psi-mi:“MI:0915”(physical association)	0.560
TMEM86B	RHBDD1	psi-mi:“MI:0915”(physical association)	0.560
NSDHL	RHBDD1	psi-mi:“MI:0915”(physical association)	0.560
RHBDD1	CMTM5	psi-mi:“MI:0915”(physical association)	0.560
RHBDD1	CGRRF1	psi-mi:“MI:0915”(physical association)	0.560
TMEM42	RHBDD1	psi-mi:“MI:0915”(physical association)	0.560
SLC66A2	RHBDD1	psi-mi:“MI:0915”(physical association)	0.560
KCNA5	TMEM223	psi-mi:“MI:0914”(association)	0.530
YIPF3	TMEM120B	psi-mi:“MI:0914”(association)	0.530
TMEM31	PSMD11	psi-mi:“MI:0914”(association)	0.530
KDELR1	TRAFD1	psi-mi:“MI:0914”(association)	0.530
GABRG2	GPAA1	psi-mi:“MI:0914”(association)	0.530
FUT3	C1QL1	psi-mi:“MI:0914”(association)	0.530
PI4K2A	GABARAP	psi-mi:“MI:0914”(association)	0.530
RHBDD1	LRRK2	psi-mi:“MI:0407”(direct interaction)	0.440
RHBDD1	DAPK1	psi-mi:“MI:0407”(direct interaction)	0.440
RHBDD1	MFHAS1	psi-mi:“MI:0407”(direct interaction)	0.440
RHBDD1	CARTPT	psi-mi:“MI:0915”(physical association)	0.400
ABCB5	RHBDD1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (384): RHBDD1 (Affinity Capture-MS), RHBDD1 (Affinity Capture-MS), RHBDD1 (Affinity Capture-MS), RHBDD1 (Affinity Capture-MS), RHBDD1 (Co-crystal Structure), VCP (Reconstituted Complex), RHBDD1 (Reconstituted Complex), RHBDD1 (Affinity Capture-MS), RHBDD1 (Affinity Capture-MS), RHBDD1 (Affinity Capture-MS), RHBDD1 (Affinity Capture-MS), RHBDD1 (Affinity Capture-MS), RHBDD1 (Affinity Capture-MS), RHBDD1 (Affinity Capture-MS), RHBDD1 (Affinity Capture-RNA)

ESM2 similar proteins: A4FUB8, E9QBI7, O35394, O95070, O97681, P15920, P58872, P58873, Q0DWA9, Q0P5E4, Q12270, Q12893, Q13488, Q1RMH4, Q28C60, Q3UVK0, Q4V8F3, Q52NJ0, Q5RBS4, Q5XIT3, Q5Z413, Q6BSA9, Q6C741, Q6CDV6, Q6CR06, Q6DCK1, Q6FSG0, Q6P6G5, Q6UPR8, Q755H8, Q7Z2K6, Q874X5, Q8BHC7, Q8BXJ9, Q8RXQ2, Q8TEB9, Q8VC82, Q8VZ96, Q91VU1, Q91XB7

Diamond homologs: Q4V8F3, Q5RBS4, Q8BHC7, Q8RXW0, Q8TEB9, Q12270, A4TGR2, A7FNW6, A9MMA7, B1JHY8, B2K5W4, B4SVM1, B4TKV0, B4TY77, B5BHH5, B5F8P0, B5FKE3, B5R383, B5R7J1, Q1C2L2, Q1CCK6, Q57IV1, Q5PLZ8, Q664J1, Q7CFX8, Q8LB17, Q8Z229, Q8ZLH5, Q9M1B5, Q755H8

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 117 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Defective CFTR causes cystic fibrosis	5	15.7×	2e-03
AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)	5	13.8×	2e-03
ABC-family protein mediated transport	6	10.4×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
regulation of membrane potential	7	16.5×	1e-04
ERAD pathway	7	12.9×	3e-04
transmembrane transport	7	12.0×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	47
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1459226	NC_000002.11:g.(?227659726)(228175684_?)del	Pathogenic

SpliceAI

2222 predictions. Top by Δscore:

Variant	Effect	Δscore
2:226836084:GAGC:G	donor_gain	1.0000
2:226836086:GC:G	donor_gain	1.0000
2:226836088:G:GG	donor_gain	1.0000
2:226836073:C:T	donor_gain	0.9900
2:226836077:T:TA	donor_gain	0.9900
2:226836083:AGAGC:A	donor_gain	0.9900
2:226836084:GAGCG:G	donor_gain	0.9900
2:226836085:AGC:A	donor_gain	0.9900
2:226836086:GCG:G	donor_gain	0.9900
2:226836086:GCGTG:G	donor_loss	0.9900
2:226836087:CGTGA:C	donor_loss	0.9900
2:226836089:TGA:T	donor_loss	0.9900
2:226836090:GAG:G	donor_loss	0.9900
2:226836091:AGTTT:A	donor_loss	0.9900
2:226865126:GGTAA:G	donor_loss	0.9900
2:226865127:G:GA	donor_loss	0.9900
2:226867185:GGA:G	acceptor_gain	0.9900
2:226867317:GG:G	donor_gain	0.9900
2:226867318:GG:G	donor_gain	0.9900
2:226869232:G:T	donor_gain	0.9900
2:226908820:AGGC:A	acceptor_gain	0.9900
2:226908821:GGCG:G	acceptor_gain	0.9900
2:226914207:GGCA:G	acceptor_gain	0.9900
2:226914348:CGAG:C	donor_loss	0.9900
2:226914350:AGGT:A	donor_loss	0.9900
2:226914352:GTAG:G	donor_loss	0.9900
2:226914353:T:A	donor_loss	0.9900
2:226839586:GGCA:G	donor_gain	0.9800
2:226869232:G:GT	donor_gain	0.9800
2:226895699:C:G	donor_gain	0.9800

AlphaMissense

2061 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:226867194:T:C	F148L	0.995
2:226867196:T:A	F148L	0.995
2:226867196:T:G	F148L	0.995
2:226906818:G:T	G198W	0.993
2:226864945:T:A	N84K	0.992
2:226864945:T:G	N84K	0.992
2:226864980:A:T	E96V	0.992
2:226867281:T:A	W177R	0.992
2:226867281:T:C	W177R	0.992
2:226864935:T:C	L81S	0.990
2:226864967:G:A	G92R	0.990
2:226864967:G:C	G92R	0.990
2:226867198:C:A	A149D	0.990
2:226906819:G:A	G198E	0.990
2:226865120:T:C	F143L	0.989
2:226865122:C:A	F143L	0.989
2:226865122:C:G	F143L	0.989
2:226864937:T:G	Y82D	0.988
2:226864981:A:C	E96D	0.988
2:226864981:A:T	E96D	0.988
2:226906818:G:A	G198R	0.987
2:226906818:G:C	G198R	0.987
2:226906830:G:A	G202R	0.987
2:226906830:G:C	G202R	0.987
2:226906831:G:A	G202E	0.987
2:226864931:C:G	H80D	0.986
2:226867291:T:A	L180H	0.986
2:226867291:T:C	L180P	0.986
2:226906816:C:A	A197D	0.986
2:226864918:T:A	H75Q	0.984

dbSNP variants (sampled 300 via entrez): RS1000013044 (2:226827846 G>C), RS1000018701 (2:226946291 T>G), RS1000026006 (2:226955746 C>G,T), RS1000067030 (2:226981305 T>G), RS1000075671 (2:226905057 G>A), RS1000089448 (2:226945303 T>C), RS1000106004 (2:226908037 A>G), RS1000121696 (2:226988117 A>T), RS1000127845 (2:226926994 G>A), RS1000128084 (2:226820991 C>T), RS1000143750 (2:226936239 T>A), RS1000196722 (2:226975160 A>G), RS1000204134 (2:226861686 G>A), RS1000210183 (2:226886744 TA>T,TAA), RS1000236111 (2:226924905 T>C)

Disease associations

OMIM: gene MIM:617515 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000106_4	Pulmonary function	5.000000e-06
GCST010796_5124	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-09
GCST010796_5125	Electrocardiogram morphology (amplitude at temporal datapoints)	7.000000e-09
GCST010796_5276	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-09
GCST90014243_6	Kawasaki disease	3.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0003892	pulmonary function measurement
EFO:0004327	electrocardiography

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs956115	RHBDD1		0.00	0
rs1896832	RHBDD1		0.00	0
rs115457081	RHBDD1	3	0.00	1	cyclophosphamide;epirubicin;fluorouracil

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	increases expression	3
bisphenol A	increases expression, increases methylation	2
sodium arsenite	increases abundance, increases expression	2
Acetaminophen	increases expression	2
Arsenic	affects methylation, increases abundance, increases expression	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Valproic Acid	decreases methylation, affects expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
arsenite	affects binding, decreases reaction	1
aflatoxin B2	decreases methylation	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	increases expression	1
monomethylarsonous acid	increases expression	1
jinfukang	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Azathioprine	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Indomethacin	increases expression	1
Aflatoxin B1	increases methylation	1
Copper Sulfate	increases expression	1
Particulate Matter	increases abundance, increases expression	1

Clinical trials (associated diseases)

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