RHBDD3

Summary

RHBDD3 (rhomboid domain containing 3, HGNC:1308) is a protein-coding gene on chromosome 22q12.2, encoding Rhomboid domain-containing protein 3 (Q9Y3P4).

Predicted to enable serine-type endopeptidase activity. Predicted to act upstream of or within several processes, including MAPK cascade; negative regulation of natural killer cell activation; and positive regulation of protein catabolic process. Predicted to be located in membrane.

Source: NCBI Gene 25807 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 90 total
• MANE Select transcript: NM_012265

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1308
Approved symbol	RHBDD3
Name	rhomboid domain containing 3
Location	22q12.2
Locus type	gene with protein product
Status	Approved
Aliases	PTAG
Ensembl gene	ENSG00000100263
Ensembl biotype	protein_coding
Entrez	25807

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 15 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000216085, ENST00000406335, ENST00000413137, ENST00000414672, ENST00000488106, ENST00000493894, ENST00000496342, ENST00000879160, ENST00000879161, ENST00000879162, ENST00000879163, ENST00000879164, ENST00000879165, ENST00000925542, ENST00000925543, ENST00000925544, ENST00000966150, ENST00000966151, ENST00000966152

RefSeq mRNA: 2 — MANE Select: NM_012265 NM_001329536, NM_012265

CCDS: CCDS13850

Canonical transcript exons

ENST00000216085 — 7 exons

Exon	Start	End
ENSE00000652008	29260702	29260864
ENSE00000652009	29263835	29264218
ENSE00000879709	29265479	29265668
ENSE00001337247	29267426	29267577
ENSE00001622623	29259872	29260237
ENSE00001759628	29267748	29267981
ENSE00003557610	29260326	29260613

Expression profiles

Bgee: expression breadth ubiquitous, 271 present calls, max score 97.51.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.4018 / max 99.4416, expressed in 1790 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
193513	5.5685	1711
193511	2.4872	1336
193514	1.6054	1025
193512	1.0521	725
193510	0.6886	378

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	97.51	gold quality
right adrenal gland	UBERON:0001233	92.84	gold quality
right testis	UBERON:0004534	92.84	gold quality
right adrenal gland cortex	UBERON:0035827	92.80	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.64	gold quality
left testis	UBERON:0004533	92.55	gold quality
cerebellar hemisphere	UBERON:0002245	92.41	gold quality
left adrenal gland cortex	UBERON:0035825	92.27	gold quality
left adrenal gland	UBERON:0001234	92.19	gold quality
cerebellar cortex	UBERON:0002129	92.19	gold quality
apex of heart	UBERON:0002098	91.52	gold quality
buccal mucosa cell	CL:0002336	91.42	gold quality
adrenal cortex	UBERON:0001235	91.30	gold quality
adenohypophysis	UBERON:0002196	90.70	gold quality
cerebellum	UBERON:0002037	90.13	gold quality
right lobe of thyroid gland	UBERON:0001119	89.55	gold quality
right frontal lobe	UBERON:0002810	89.49	gold quality
testis	UBERON:0000473	89.48	gold quality
adrenal gland	UBERON:0002369	89.40	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	89.22	gold quality
mucosa of transverse colon	UBERON:0004991	89.12	gold quality
pituitary gland	UBERON:0000007	89.02	gold quality
metanephros cortex	UBERON:0010533	88.79	gold quality
right uterine tube	UBERON:0001302	88.72	gold quality
cingulate cortex	UBERON:0003027	88.32	gold quality
gastrocnemius	UBERON:0001388	88.29	gold quality
left lobe of thyroid gland	UBERON:0001120	88.22	gold quality
anterior cingulate cortex	UBERON:0009835	88.22	gold quality
ventricular zone	UBERON:0003053	88.15	gold quality
nucleus accumbens	UBERON:0001882	87.92	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.29

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

1 targeting RHBDD3, 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-29B-1-5P	98.86	68.35	1364

Literature-anchored findings (GeneRIF, showing 4)

• isolation of a novel differentially methylated chromosome 22 CpG island-associated gene PTAG (PMID:15105437)
• Loss of PTAG contributes to a blunted apoptotic response and is likely to predispose cells toward malignant transformation and resistance to chemotherapeutic interventions. (PMID:17117413)
• the EWSR1 promoter functions in a bidirectional manner, thereby regulating also RHBDD3 (PMID:19212622)
• RHBDD3 is a target gene of the BACH1 transcription factor according to ChIP-seq analysis in HEK 293 cells. (PMID:21555518)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	rhbdd3	ENSDARG00000079816
mus_musculus	Rhbdd3	ENSMUSG00000034175
rattus_norvegicus	Rhbdd3	ENSRNOG00000027032

Paralogs (2): RHBDD2 (ENSG00000005486), RHBDD1 (ENSG00000144468)

Protein

Protein identifiers

Rhomboid domain-containing protein 3 — Q9Y3P4 (reviewed: Q9Y3P4)

All UniProt accessions (4): Q9Y3P4, B0QYJ1, B0QYJ2, F8WFA9

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Membrane.

RefSeq proteins (2): NP_001316465, NP_036397* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009060	UBA-like_sf	Homologous_superfamily
IPR015940	UBA	Domain
IPR022764	Peptidase_S54_rhomboid_dom	Domain
IPR035952	Rhomboid-like_sf	Homologous_superfamily

Pfam: PF00627, PF01694

UniProt features (9 total): transmembrane region 5, sequence variant 2, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y3P4-F1	69.46	0.15

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 159 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, RNGTGGGC_UNKNOWN, AP1_01, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, TGCGCANK_UNKNOWN, GOBP_INFLAMMATORY_RESPONSE, CMYB_01, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, PATIL_LIVER_CANCER, GOBP_REGULATION_OF_ACUTE_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_PROTEIN_SECRETION, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_REGULATION_OF_NATURAL_KILLER_CELL_ACTIVATION

GO Biological Process (7): MAPK cascade (GO:0000165), liver development (GO:0001889), regulation of acute inflammatory response (GO:0002673), response to xenobiotic stimulus (GO:0009410), negative regulation of natural killer cell activation (GO:0032815), positive regulation of protein catabolic process (GO:0045732), regulation of protein secretion (GO:0050708)

GO Molecular Function (2): serine-type endopeptidase activity (GO:0004252), protein binding (GO:0005515)

GO Cellular Component (1): membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular signaling cassette	1
gland development	1
hepaticobiliary system development	1
acute inflammatory response	1
regulation of inflammatory response	1
response to chemical	1
natural killer cell activation	1
regulation of natural killer cell activation	1
negative regulation of lymphocyte activation	1
positive regulation of catabolic process	1
protein catabolic process	1
regulation of protein catabolic process	1
positive regulation of protein metabolic process	1
protein secretion	1
regulation of protein transport	1
regulation of secretion by cell	1
endopeptidase activity	1
serine-type peptidase activity	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

702 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RHBDD3	RHBDL1	O75783	556
RHBDD3	UBAC2	Q8NBM4	535
RHBDD3	RHBDD2	Q6NTF9	503
RHBDD3	RHBDD1	Q8TEB9	490
RHBDD3	RHBDF1	Q96CC6	490
RHBDD3	SIRAL2	Q9NWS6	479
RHBDD3	RHBDL3	P58872	476
RHBDD3	LETM2	Q2VYF4	461
RHBDD3	RNF112	Q9ULX5	448
RHBDD3	REEP6	Q96HR9	441
RHBDD3	RHBDF2	Q6PJF5	431
RHBDD3	RHBDL2	Q9NX52	430
RHBDD3	GPAT2	Q6NUI2	423
RHBDD3	DNAJC18	Q9H819	423
RHBDD3	BBS9	P78514	408

IntAct

34 interactions, top by confidence:

A	B	Type	Score
ENTREP1	WWP2	psi-mi:“MI:0914”(association)	0.850
KCNA5	TMEM223	psi-mi:“MI:0914”(association)	0.530
GPR21	TMEM120B	psi-mi:“MI:0914”(association)	0.530
LRRC8B	SLC25A17	psi-mi:“MI:0914”(association)	0.530
TGOLN2	DENND11	psi-mi:“MI:0914”(association)	0.530
TMEM31	PSMD11	psi-mi:“MI:0914”(association)	0.530
IL27RA	B4GALT5	psi-mi:“MI:0914”(association)	0.530
ENTREP3	NEDD4	psi-mi:“MI:0914”(association)	0.530
FAM189B	KLRG2	psi-mi:“MI:0914”(association)	0.350
TGOLN2	DENND11	psi-mi:“MI:0914”(association)	0.350
SLC18A1	LIMK2	psi-mi:“MI:0914”(association)	0.350
SLC17A2	PSMD11	psi-mi:“MI:0914”(association)	0.350
IL27RA	NRP1	psi-mi:“MI:0914”(association)	0.350
HTR3A	GPAA1	psi-mi:“MI:0914”(association)	0.350
FNDC5	CAPN15	psi-mi:“MI:0914”(association)	0.350
rep	GPR89A	psi-mi:“MI:0914”(association)	0.350
BSCL2	TMEM223	psi-mi:“MI:0914”(association)	0.350
CHRNB4	GPR89A	psi-mi:“MI:0914”(association)	0.350
SLC18A1	UBXN8	psi-mi:“MI:0914”(association)	0.350
SLC17A2	ABCD4	psi-mi:“MI:0914”(association)	0.350
HTR3A	EXTL3	psi-mi:“MI:0914”(association)	0.350
KCNC3	ATF6	psi-mi:“MI:0914”(association)	0.350
POPDC2	ANK2	psi-mi:“MI:0914”(association)	0.350
NIPA1	UNC119B	psi-mi:“MI:0914”(association)	0.350

BioGRID (57): RHBDD3 (Affinity Capture-MS), RHBDD3 (Affinity Capture-MS), RHBDD3 (Affinity Capture-MS), RHBDD3 (Affinity Capture-MS), RHBDD3 (Affinity Capture-MS), RHBDD3 (Affinity Capture-MS), RHBDD3 (Proximity Label-MS), RHBDD3 (Affinity Capture-MS), RHBDD3 (Affinity Capture-MS), RHBDD3 (Affinity Capture-MS), RHBDD3 (Affinity Capture-MS), RHBDD3 (Affinity Capture-MS), RHBDD3 (Affinity Capture-MS), RHBDD3 (Affinity Capture-MS), RHBDD3 (Affinity Capture-MS)

ESM2 similar proteins: A1L515, A4D2P6, A6QQD2, A8VU90, E1BDF2, O75808, O88995, P0CG25, P22083, Q0IIA6, Q2TA57, Q3B7L1, Q3MIP1, Q3U5Q7, Q3UR50, Q3UR97, Q3UV16, Q400G9, Q5BKX5, Q5EBM0, Q5GH72, Q5SZI1, Q5TM19, Q5U4P2, Q62994, Q659K9, Q6PRD1, Q7Z736, Q861W0, Q86UR1, Q8BNN1, Q8C0R7, Q8CG70, Q8IUW3, Q8IVL6, Q8N398, Q8NAG6, Q8NCW0, Q8R2H1, Q8VCE9

Diamond homologs: Q642B3, Q8BP97, Q9Y3P4

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 44 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.

GO biological processes:

GO term	Partners	Fold	FDR
regulation of membrane potential	5	33.0×	1e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	69
Likely benign	10
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1197 predictions. Top by Δscore:

Variant	Effect	Δscore
22:29260235:AGCC:A	acceptor_loss	1.0000
22:29260236:GC:G	acceptor_gain	1.0000
22:29260237:CC:C	acceptor_gain	1.0000
22:29260237:CCTG:C	acceptor_loss	1.0000
22:29260238:C:CG	acceptor_loss	1.0000
22:29260239:T:A	acceptor_loss	1.0000
22:29260247:G:C	acceptor_gain	1.0000
22:29260247:G:GC	acceptor_gain	1.0000
22:29265449:T:TA	donor_gain	1.0000
22:29267476:T:TA	donor_gain	1.0000
22:29267746:A:AC	donor_gain	1.0000
22:29267747:C:CC	donor_gain	1.0000
22:29267747:CTG:C	donor_gain	1.0000
22:29260234:CAGC:C	acceptor_gain	0.9900
22:29260238:C:CC	acceptor_gain	0.9900
22:29260320:CCTTA:C	donor_loss	0.9900
22:29260321:CTTAC:C	donor_loss	0.9900
22:29260322:TTAC:T	donor_loss	0.9900
22:29260323:TA:T	donor_loss	0.9900
22:29260324:A:AC	donor_gain	0.9900
22:29260325:C:CC	donor_gain	0.9900
22:29260325:C:CT	donor_loss	0.9900
22:29260325:CCG:C	donor_gain	0.9900
22:29265477:AC:A	donor_gain	0.9900
22:29265478:CC:C	donor_gain	0.9900
22:29265669:C:CC	acceptor_gain	0.9900
22:29267429:A:AC	donor_gain	0.9900
22:29267430:C:CC	donor_gain	0.9900
22:29267573:CCCTT:C	acceptor_gain	0.9900
22:29267574:CCTTC:C	acceptor_gain	0.9900

AlphaMissense

2374 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:29260211:A:G	F337S	0.998
22:29260210:G:C	F337L	0.997
22:29260210:G:T	F337L	0.997
22:29260212:A:G	F337L	0.997
22:29260211:A:C	F337C	0.993
22:29260145:A:G	L359S	0.991
22:29260226:A:G	L332P	0.991
22:29264160:G:C	S69R	0.990
22:29264160:G:T	S69R	0.990
22:29264162:T:G	S69R	0.990
22:29260226:A:T	L332Q	0.984
22:29260217:A:G	M335T	0.983
22:29260157:G:T	A355D	0.982
22:29260179:C:G	A348P	0.980
22:29260338:A:T	V324D	0.979
22:29260407:A:G	I301T	0.979
22:29260216:C:A	M335I	0.978
22:29260216:C:G	M335I	0.978
22:29260216:C:T	M335I	0.978
22:29260187:G:T	A345E	0.976
22:29260235:A:G	L329P	0.976
22:29265549:G:C	S26R	0.976
22:29265549:G:T	S26R	0.976
22:29265551:T:G	S26R	0.976
22:29260197:C:G	A342P	0.974
22:29260182:C:G	A347P	0.971
22:29260212:A:C	F337V	0.971
22:29264126:C:T	E81K	0.971
22:29260158:C:G	A355P	0.968
22:29260184:A:G	L346P	0.968

dbSNP variants (sampled 300 via entrez): RS1000112688 (22:29262822 T>C), RS1000187053 (22:29266814 T>G), RS1000218198 (22:29267045 A>G), RS1000233730 (22:29268585 C>G,T), RS1000680622 (22:29260059 G>C,T), RS1001070856 (22:29269552 A>C), RS1001208553 (22:29260978 T>TCCTCA), RS1001540866 (22:29270020 C>T), RS1001544899 (22:29269750 C>G), RS1001582614 (22:29260826 G>A), RS1001671337 (22:29266141 A>C,G), RS1001852049 (22:29269335 A>C,G,T), RS1002415100 (22:29265950 C>A,T), RS1002794343 (22:29268048 G>C), RS1003460540 (22:29268450 C>A,T)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001937_28	Breast cancer	3.000000e-09
GCST002553_2	Pancreatic cancer	1.000000e-08

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, increases expression	2
aristolochic acid I	increases expression	1
beta-lapachone	decreases expression	1
cobaltous chloride	increases expression	1
tamibarotene	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
abrine	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Arsenic	affects methylation	1
Atrazine	decreases expression	1
Cisplatin	decreases expression	1
Plant Extracts	decreases expression, affects cotreatment	1
Quercetin	increases expression	1
Selenium	increases expression	1
Smoke	decreases expression	1
Tretinoin	decreases expression	1
Cyclosporine	increases expression	1
Vitamin K 3	affects expression	1

Clinical trials (associated diseases)

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