RHBDD2

Summary

RHBDD2 (rhomboid domain containing 2, HGNC:23082) is a protein-coding gene on chromosome 7q11.23, encoding Rhomboid domain-containing protein 2 (Q6NTF9).

The protein encoded by this gene is a member of the rhomboid family of membrane-bound proteases and is overexpressed in some breast cancers. Members of this family are involved in intramembrane proteolysis. In mouse, the orthologous protein associates with the Golgi body.

Source: NCBI Gene 57414 — RefSeq curated summary.

At a glance

• GWAS associations: 14
• Clinical variants (ClinVar): 84 total
• MANE Select transcript: NM_001040456

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23082
Approved symbol	RHBDD2
Name	rhomboid domain containing 2
Location	7q11.23
Locus type	gene with protein product
Status	Approved
Aliases	NPD007
Ensembl gene	ENSG00000005486
Ensembl biotype	protein_coding
OMIM	615203
Entrez	57414

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 6 protein_coding, 5 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000006777, ENST00000318622, ENST00000428119, ENST00000454791, ENST00000466232, ENST00000467406, ENST00000468304, ENST00000468644, ENST00000476218, ENST00000873333, ENST00000873334, ENST00000873335

RefSeq mRNA: 6 — MANE Select: NM_001040456 NM_001040456, NM_001040457, NM_001346186, NM_001346187, NM_001346188, NM_001346189

CCDS: CCDS43602, CCDS43603

Canonical transcript exons

ENST00000006777 — 4 exons

Exon	Start	End
ENSE00001484646	75887992	75888926
ENSE00002525782	75879034	75879260
ENSE00003611549	75883698	75883848
ENSE00003642362	75881829	75882236

Expression profiles

Bgee: expression breadth ubiquitous, 249 present calls, max score 99.30.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 63.9467 / max 609.5162, expressed in 1815 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
79125	52.1243	1813
79124	5.9339	1664
79123	5.0694	1586
79126	0.4010	174
79130	0.1963	94
79129	0.1665	64
79127	0.0552	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adenohypophysis	UBERON:0002196	99.30	gold quality
pituitary gland	UBERON:0000007	99.15	gold quality
nucleus accumbens	UBERON:0001882	99.05	gold quality
hypothalamus	UBERON:0001898	98.95	gold quality
prefrontal cortex	UBERON:0000451	98.91	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.86	gold quality
right adrenal gland cortex	UBERON:0035827	98.83	gold quality
putamen	UBERON:0001874	98.80	gold quality
right frontal lobe	UBERON:0002810	98.80	gold quality
anterior cingulate cortex	UBERON:0009835	98.79	gold quality
caudate nucleus	UBERON:0001873	98.78	gold quality
right adrenal gland	UBERON:0001233	98.73	gold quality
left adrenal gland	UBERON:0001234	98.68	gold quality
left adrenal gland cortex	UBERON:0035825	98.68	gold quality
amygdala	UBERON:0001876	98.62	gold quality
adrenal cortex	UBERON:0001235	98.56	gold quality
frontal cortex	UBERON:0001870	98.42	gold quality
frontal lobe	UBERON:0016525	98.42	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	98.40	gold quality
adrenal gland	UBERON:0002369	98.39	gold quality
Ammon’s horn	UBERON:0001954	98.14	gold quality
neocortex	UBERON:0001950	98.09	gold quality
adrenal tissue	UBERON:0018303	97.91	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	97.90	gold quality
forebrain	UBERON:0001890	97.86	gold quality
cerebral cortex	UBERON:0000956	97.79	gold quality
temporal lobe	UBERON:0001871	97.78	gold quality
superior vestibular nucleus	UBERON:0007227	97.70	gold quality
kidney epithelium	UBERON:0004819	97.56	gold quality
metanephros cortex	UBERON:0010533	97.52	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	24.54
E-MTAB-9067	yes	11.30
E-HCAD-25	yes	9.16
E-MTAB-7606	no	1899.44
E-CURD-10	no	304.25
E-CURD-120	no	31.28
E-MTAB-6678	no	3.39
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 8)

• RHBDD2 over-expression behaves as an indicator of poor prognosis and may play a role facilitating breast cancer progression. (PMID:19616622)
• Increased RHBDD2 expression in response to the chemotherapy is associated with advanced stages of colorectal cancer. (PMID:22965880)
• RHBDD2 protein plays important roles in the development and normal function of the retina (PMID:23386608)
• RHBDD2 overexpression in breast cancer could represent an adaptive phenotype to the stressful tumor microenvironment by modulating the endoplasmic reticulum stress response. (PMID:24078384)
• Quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis showed a significant RHBDD2 mRNA overexpression in advanced breast cancer compared with normal tissue samples (p = 0.012). (PMID:24185965)
• The RHBDD2 subcellular localization was corroborated at the Golgi apparatus. (PMID:29901166)
• RHBDD2 overexpression promotes a chemoresistant and invasive phenotype to rectal cancer tumors via modulating UPR and focal adhesion genes. (PMID:32339641)
• RHBDD2WWOX protein interaction during proliferative and differentiated stages in normal and breast cancer cells. (PMID:34109992)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	rhbdd2	ENSDARG00000092463
mus_musculus	Rhbdd2	ENSMUSG00000039917
rattus_norvegicus	Rhbdd2	ENSRNOG00000001443

Paralogs (2): RHBDD3 (ENSG00000100263), RHBDD1 (ENSG00000144468)

Protein

Protein identifiers

Rhomboid domain-containing protein 2 — Q6NTF9 (reviewed: Q6NTF9)

All UniProt accessions (2): Q6NTF9, Q9UDT1

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Golgi apparatus. cis-Golgi network membrane.

Similarity. Belongs to the peptidase S54 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q6NTF9-1	1	yes
Q6NTF9-2	2
Q6NTF9-3	3

RefSeq proteins (6): NP_001035546, NP_001035547, NP_001333115, NP_001333116, NP_001333117, NP_001333118 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR022764	Peptidase_S54_rhomboid_dom	Domain
IPR035952	Rhomboid-like_sf	Homologous_superfamily

Pfam: PF01694

UniProt features (15 total): transmembrane region 5, splice variant 2, sequence conflict 2, region of interest 2, compositionally biased region 2, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6NTF9-F1	68.67	0.19

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 85 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_TOPOLOGICALLY_INCORRECT_PROTEIN, chr7q11, GOBP_PROTEASOMAL_PROTEIN_CATABOLIC_PROCESS, GOBP_ERAD_PATHWAY, CAGCCTC_MIR4855P, GOBP_PROTEIN_CATABOLIC_PROCESS, GOBP_RESPONSE_TO_TOPOLOGICALLY_INCORRECT_PROTEIN, GOCC_NUCLEAR_OUTER_MEMBRANE_ENDOPLASMIC_RETICULUM_MEMBRANE_NETWORK, GOBP_PROTEOLYSIS, GOCC_ORGANELLE_SUBCOMPARTMENT, GOMF_PEPTIDASE_ACTIVITY, GOMF_RIBONUCLEOPROTEIN_COMPLEX_BINDING

GO Biological Process (2): endoplasmic reticulum unfolded protein response (GO:0030968), ERAD pathway (GO:0036503)

GO Molecular Function (3): serine-type endopeptidase activity (GO:0004252), signal recognition particle binding (GO:0005047), protein binding (GO:0005515)

GO Cellular Component (6): Golgi membrane (GO:0000139), nucleoplasm (GO:0005654), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), perinuclear region of cytoplasm (GO:0048471), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
response to endoplasmic reticulum stress	2
cytoplasm	2
cellular response to unfolded protein	1
intracellular signal transduction	1
proteasomal protein catabolic process	1
response to chemical	1
endopeptidase activity	1
serine-type peptidase activity	1
ribonucleoprotein complex binding	1
binding	1
Golgi apparatus	1
bounding membrane of organelle	1
nuclear lumen	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

792 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RHBDD2	RHBDF1	Q96CC6	667
RHBDD2	RHBDD1	Q8TEB9	634
RHBDD2	RHBDL1	O75783	587
RHBDD2	UBAC2	Q8NBM4	573
RHBDD2	RHBDL2	Q9NX52	567
RHBDD2	PKD1L1	Q8TDX9	513
RHBDD2	ANO7	Q6IWH7	506
RHBDD2	RHBDD3	Q9Y3P4	503
RHBDD2	A0A1W2PP11	A0A1W2PP11	500
RHBDD2	PARL	Q9H300	499
RHBDD2	RHBDF2	Q6PJF5	490
RHBDD2	RHBDL3	P58872	474
RHBDD2	KANK1	Q14678	466
RHBDD2	BROX	Q5VW32	459
RHBDD2	ZBTB34	Q8NCN2	424

IntAct

39 interactions, top by confidence:

A	B	Type	Score
IFT70B	IFT56	psi-mi:“MI:0914”(association)	0.790
IFT27	IFT56	psi-mi:“MI:0914”(association)	0.690
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
NEDD4	RHBDD2	psi-mi:“MI:0407”(direct interaction)	0.440
YAP1	RHBDD2	psi-mi:“MI:0407”(direct interaction)	0.440
GPC1	SNAP23	psi-mi:“MI:0915”(physical association)	0.400
GPC1	GANAB	psi-mi:“MI:0915”(physical association)	0.400
RHBDD2	ADORA2A	psi-mi:“MI:0915”(physical association)	0.370
RHBDD2	CCR9	psi-mi:“MI:0915”(physical association)	0.370
RHBDD2	DRD2	psi-mi:“MI:0915”(physical association)	0.370
RHBDD2	CHRM4	psi-mi:“MI:0915”(physical association)	0.370
RHBDD2	PTAFR	psi-mi:“MI:0915”(physical association)	0.370
ERBB2	RHBDD2	psi-mi:“MI:0915”(physical association)	0.370
PB1	ESYT2	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
PSEN1	PGRMC1	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
	TMEM223	psi-mi:“MI:0914”(association)	0.350
STK32C	ILVBL	psi-mi:“MI:0914”(association)	0.350
CCDC47	ESYT2	psi-mi:“MI:0914”(association)	0.350
HLA-B	RAB29	psi-mi:“MI:0914”(association)	0.350
AFG2A	ESYT2	psi-mi:“MI:0914”(association)	0.350
PCDHGB4	AAMP	psi-mi:“MI:0914”(association)	0.350
SETD6	GFPT2	psi-mi:“MI:0914”(association)	0.350
SLC39A14	ESYT2	psi-mi:“MI:0914”(association)	0.350
P/V	ESYT2	psi-mi:“MI:0914”(association)	0.350
TCTN3	TMEM120B	psi-mi:“MI:2364”(proximity)	0.270
TMEM17	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
TCTN2	TMEM120B	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (129): RHBDD2 (Proximity Label-MS), RHBDD2 (Proximity Label-MS), RHBDD2 (Proximity Label-MS), RHBDD2 (Proximity Label-MS), RHBDD2 (Affinity Capture-MS), IFT27 (Affinity Capture-MS), RHBDD2 (Affinity Capture-MS), RHBDD2 (Affinity Capture-MS), RHBDD2 (Affinity Capture-MS), RHBDD2 (Affinity Capture-MS), RHBDD2 (Proximity Label-MS), RHBDD2 (Proximity Label-MS), RHBDD2 (Proximity Label-MS), RHBDD2 (Affinity Capture-MS), IL32 (Two-hybrid)

ESM2 similar proteins: A0A140LI67, A0JPN4, A2A6C4, A2VDJ0, A6NDA9, O43187, O54714, O70167, O70173, O70260, O75783, P60924, Q08DV9, Q14154, Q1L981, Q2YDQ5, Q32LT7, Q3SZT1, Q3U3D7, Q498W5, Q49LS3, Q4QQS0, Q4V832, Q5GH66, Q5HZK2, Q5R810, Q6AYL2, Q6INB3, Q6IRN0, Q6JWV8, Q6NTF9, Q6P4K6, Q6P6V6, Q6PFC5, Q6PJF5, Q6R5J1, Q6UX68, Q70CQ4, Q8CFA1, Q8CIP5

Diamond homologs: Q6NTF9, Q8VEK2

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 43 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
Neutrophil degranulation	6	4.2×	9e-03

GO biological processes:

GO term	Partners	Fold	FDR
smoothened signaling pathway	5	23.8×	5e-04
cilium assembly	7	13.6×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	70
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

929 predictions. Top by Δscore:

Variant	Effect	Δscore
7:75879259:AGG:A	donor_loss	1.0000
7:75879260:GGT:G	donor_loss	1.0000
7:75882032:G:GT	donor_gain	1.0000
7:75882032:G:T	donor_gain	1.0000
7:75882080:G:GT	donor_gain	1.0000
7:75879256:GCAAG:G	donor_gain	0.9900
7:75879261:G:GG	donor_gain	0.9900
7:75881419:T:G	donor_gain	0.9900
7:75882020:TCA:T	donor_gain	0.9900
7:75882026:C:G	donor_gain	0.9900
7:75882041:G:GT	donor_gain	0.9900
7:75882080:G:T	donor_gain	0.9900
7:75882103:G:GT	donor_gain	0.9900
7:75882104:A:G	donor_gain	0.9900
7:75882132:T:TA	donor_gain	0.9900
7:75882204:G:GG	donor_gain	0.9900
7:75879259:AG:A	donor_gain	0.9800
7:75879260:GG:G	donor_gain	0.9800
7:75881416:GTGT:G	donor_gain	0.9800
7:75881417:TGTT:T	donor_gain	0.9800
7:75881827:A:AG	acceptor_gain	0.9800
7:75881828:G:GG	acceptor_gain	0.9800
7:75881963:A:AG	donor_gain	0.9800
7:75882005:G:GT	donor_gain	0.9800
7:75882048:G:GT	donor_gain	0.9800
7:75882110:C:T	donor_gain	0.9800
7:75882133:T:TA	donor_gain	0.9800
7:75879257:C:T	donor_gain	0.9700
7:75881358:T:TA	acceptor_gain	0.9700
7:75882127:C:T	donor_gain	0.9700

AlphaMissense

2304 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:75881933:G:C	G95R	0.998
7:75881934:G:A	G95D	0.998
7:75881934:G:T	G95V	0.998
7:75882227:G:A	G193R	0.998
7:75882227:G:C	G193R	0.998
7:75882227:G:T	G193W	0.998
7:75882228:G:A	G193E	0.998
7:75881922:A:T	E91V	0.997
7:75882155:T:A	W169R	0.997
7:75882155:T:C	W169R	0.997
7:75882215:G:T	G189W	0.997
7:75882216:G:A	G189E	0.997
7:75881933:G:T	G95C	0.996
7:75882050:G:C	G134R	0.996
7:75882053:T:C	F135L	0.996
7:75882054:T:C	F135S	0.996
7:75882055:C:A	F135L	0.996
7:75882055:C:G	F135L	0.996
7:75882072:C:A	A141D	0.996
7:75882215:G:A	G189R	0.996
7:75882215:G:C	G189R	0.996
7:75881923:G:C	E91D	0.995
7:75881923:G:T	E91D	0.995
7:75882080:G:A	G144R	0.995
7:75882080:G:C	G144R	0.995
7:75882066:C:A	A139D	0.994
7:75881937:C:T	T96I	0.993
7:75881922:A:C	E91A	0.992
7:75881948:T:C	C100R	0.992
7:75882212:T:C	C188R	0.992

dbSNP variants (sampled 300 via entrez): RS1000275251 (7:75878761 C>A), RS1000557316 (7:75877482 G>T), RS1000604572 (7:75877158 G>A), RS1000872592 (7:75888481 T>G), RS1001147942 (7:75883078 C>A,T), RS1001281451 (7:75879960 T>A), RS1001455018 (7:75883259 G>A,T), RS1001822124 (7:75885451 G>A,C), RS1001928103 (7:75889142 A>G), RS1002559285 (7:75884033 C>T), RS1003622913 (7:75881375 A>G), RS1004999696 (7:75885432 G>A), RS1005595300 (7:75882556 C>A), RS1005669422 (7:75887882 A>G), RS1005680666 (7:75887571 G>A)

Disease associations

OMIM: gene MIM:615203 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST004600_35	Eosinophil percentage of white cells	1.000000e-35
GCST004600_36	Eosinophil percentage of white cells	6.000000e-15
GCST004606_158	Eosinophil count	1.000000e-31
GCST004606_159	Eosinophil count	5.000000e-14
GCST004617_11	Eosinophil percentage of granulocytes	2.000000e-32
GCST004617_12	Eosinophil percentage of granulocytes	3.000000e-13
GCST004623_111	Neutrophil percentage of granulocytes	2.000000e-30
GCST004623_112	Neutrophil percentage of granulocytes	4.000000e-12
GCST004624_117	Sum eosinophil basophil counts	2.000000e-29
GCST004624_118	Sum eosinophil basophil counts	4.000000e-13
GCST008361_9	Response to cognitive-behavioural therapy in major depressive disorder	6.000000e-06
GCST90002381_236	Eosinophil count	9.000000e-43
GCST90002381_237	Eosinophil count	1.000000e-16
GCST90002382_150	Eosinophil percentage of white cells	4.000000e-22

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004842	eosinophil count
EFO:0007996	eosinophil percentage of granulocytes
EFO:0007994	neutrophil percentage of granulocytes
EFO:0005090	basophil count
EFO:0007820	cognitive behavioural therapy

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	increases expression	3
Benzo(a)pyrene	affects methylation, increases expression	3
bisphenol A	affects expression, increases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, increases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Tunicamycin	increases expression	2
Valproic Acid	increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	2
Aflatoxin B1	affects cotreatment, increases expression, increases methylation	2
Cadmium Chloride	increases expression	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
sodium arsenite	increases expression	1
cobaltous chloride	increases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	increases expression, affects cotreatment	1
CGP 52608	affects binding, increases reaction	1
corosolic acid	increases expression	1
monomethylarsonous acid	increases expression	1
dimethylarsinous acid	increases expression	1
Zoledronic Acid	increases expression	1
Acrolein	increases oxidation, increases abundance, affects cotreatment	1
Air Pollutants, Occupational	increases expression	1
Vehicle Emissions	decreases expression, increases abundance	1
Benzene	increases expression	1
Diethylstilbestrol	decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_TI95	HAP1 RHBDD2 (-) 1	Cancer cell line	Male
CVCL_TI96	HAP1 RHBDD2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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