RHBDL3

Summary

RHBDL3 (rhomboid like 3, HGNC:16502) is a protein-coding gene on chromosome 17q11.2, encoding Rhomboid-related protein 3 (P58872). May be involved in regulated intramembrane proteolysis and the subsequent release of functional polypeptides from their membrane anchors.

Predicted to enable serine-type endopeptidase activity. Predicted to be involved in proteolysis. Predicted to be located in membrane.

Source: NCBI Gene 162494 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 68 total
• MANE Select transcript: NM_138328

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16502
Approved symbol	RHBDL3
Name	rhomboid like 3
Location	17q11.2
Locus type	gene with protein product
Status	Approved
Aliases	VRHO
Ensembl gene	ENSG00000141314
Ensembl biotype	protein_coding
OMIM	619017
Entrez	162494

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 13 protein_coding, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000269051, ENST00000431505, ENST00000536287, ENST00000538145, ENST00000578006, ENST00000582967, ENST00000918442, ENST00000918443, ENST00000918444, ENST00000918445, ENST00000918446, ENST00000918447, ENST00000968675, ENST00000968676, ENST00000968677

RefSeq mRNA: 5 — MANE Select: NM_138328 NM_001330181, NM_001363834, NM_001363835, NM_001363836, NM_138328

CCDS: CCDS32613, CCDS82103, CCDS92287

Canonical transcript exons

ENST00000269051 — 9 exons

Exon	Start	End
ENSE00001122891	32284659	32284817
ENSE00001122899	32267902	32267925
ENSE00002344308	32320958	32324659
ENSE00003532442	32294294	32294442
ENSE00003596163	32305341	32305441
ENSE00003621859	32316232	32316292
ENSE00003634007	32298092	32298204
ENSE00003760026	32288792	32289016
ENSE00003848406	32265832	32266300

Expression profiles

Bgee: expression breadth ubiquitous, 148 present calls, max score 85.51.

FANTOM5 (CAGE): breadth broad, TPM avg 0.5388 / max 22.5425, expressed in 237 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
160227	0.5388	237

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right frontal lobe	UBERON:0002810	85.51	gold quality
Brodmann (1909) area 9	UBERON:0013540	84.94	gold quality
right atrium auricular region	UBERON:0006631	84.20	gold quality
anterior cingulate cortex	UBERON:0009835	83.78	gold quality
cardiac atrium	UBERON:0002081	83.09	gold quality
prefrontal cortex	UBERON:0000451	82.15	gold quality
neocortex	UBERON:0001950	79.40	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	79.36	gold quality
primary visual cortex	UBERON:0002436	78.75	gold quality
frontal cortex	UBERON:0001870	78.62	gold quality
right hemisphere of cerebellum	UBERON:0014890	78.58	gold quality
cortical plate	UBERON:0005343	78.26	gold quality
cerebellar hemisphere	UBERON:0002245	78.15	gold quality
ganglionic eminence	UBERON:0004023	77.95	gold quality
hypothalamus	UBERON:0001898	77.94	gold quality
cerebellar cortex	UBERON:0002129	77.88	gold quality
amygdala	UBERON:0001876	77.70	gold quality
putamen	UBERON:0001874	77.35	gold quality
right adrenal gland cortex	UBERON:0035827	77.13	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.06	gold quality
ventricular zone	UBERON:0003053	76.56	gold quality
right adrenal gland	UBERON:0001233	76.30	gold quality
cerebral cortex	UBERON:0000956	76.28	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	75.60	gold quality
cerebellum	UBERON:0002037	75.45	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	75.09	gold quality
Ammon’s horn	UBERON:0001954	74.59	gold quality
caudate nucleus	UBERON:0001873	74.50	gold quality
left adrenal gland	UBERON:0001234	73.89	gold quality
forebrain	UBERON:0001890	73.74	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.42

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

140 targeting RHBDL3, 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-8485	100.00	77.57	4731
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-5692A	100.00	74.40	6850
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4728-5P	99.85	69.39	4718

Literature-anchored findings (GeneRIF, showing 1)

• The mammalian rhomboid protein RHBDL4 protects against endoplasmic reticulum stress by regulating the morphology and distribution of ER sheets. (PMID:35436469)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
danio_rerio	rhbdl3	ENSDARG00000105190
mus_musculus	Rhbdl3	ENSMUSG00000017692
rattus_norvegicus	Rhbdl3	ENSRNOG00000005515
drosophila_melanogaster	ru	FBGN0003295
drosophila_melanogaster	rho	FBGN0004635
drosophila_melanogaster	stet	FBGN0020248
drosophila_melanogaster	rho-6	FBGN0032415
drosophila_melanogaster	rho-5	FBGN0041723
caenorhabditis_elegans		WBGENE00004401
caenorhabditis_elegans		WBGENE00004402
caenorhabditis_elegans		WBGENE00004403

Paralogs (5): RHBDF1 (ENSG00000007384), RHBDL1 (ENSG00000103269), RHBDF2 (ENSG00000129667), RHBDL2 (ENSG00000158315), PARL (ENSG00000175193)

Protein

Protein identifiers

Rhomboid-related protein 3 — P58872 (reviewed: P58872)

Alternative names: Ventrhoid transmembrane protein

All UniProt accessions (3): A4FU16, P58872, J3QQX4

UniProt curated annotations — full annotation on UniProt →

Function. May be involved in regulated intramembrane proteolysis and the subsequent release of functional polypeptides from their membrane anchors.

Subcellular location. Membrane.

Similarity. Belongs to the peptidase S54 family.

Isoforms (3)

UniProt ID	Names	Canonical?
P58872-1	1	yes
P58872-2	2
P58872-3	3

RefSeq proteins (5): NP_001317110, NP_001350763, NP_001350764, NP_001350765, NP_612201* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR017213	Peptidase_S54_rhomboid_met	Family
IPR022764	Peptidase_S54_rhomboid_dom	Domain
IPR035952	Rhomboid-like_sf	Homologous_superfamily
IPR051739	Rhomboid_IM_Serine_Proteases	Family

Pfam: PF01694, PF13499

UniProt features (15 total): transmembrane region 7, active site 2, splice variant 2, domain 2, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P58872-F1	79.68	0.41

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): 278 (nucleophile); 343

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 115 (showing top): RNGTGGGC_UNKNOWN, CHX10_01, chr17q11, MARTORIATI_MDM4_TARGETS_NEUROEPITHELIUM_DN, MARTINEZ_RB1_TARGETS_DN, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_DN, LYF1_01, GATA1_02, BIDUS_METASTASIS_UP, TGCCTTA_MIR124A, HOXA4_Q2, EVI1_04, TAATTA_CHX10_01, GOBP_PROTEOLYSIS, GOMF_PEPTIDASE_ACTIVITY

GO Biological Process (1): proteolysis (GO:0006508)

GO Molecular Function (5): serine-type endopeptidase activity (GO:0004252), calcium ion binding (GO:0005509), peptidase activity (GO:0008233), serine-type peptidase activity (GO:0008236), hydrolase activity (GO:0016787)

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein metabolic process	1
endopeptidase activity	1
serine-type peptidase activity	1
metal ion binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
serine hydrolase activity	1
catalytic activity	1
cellular anatomical structure	1

Protein interactions and networks

STRING

3751 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RHBDL3	RHBDD1	Q8TEB9	602
RHBDL3	A0A1W2PP11	A0A1W2PP11	529
RHBDL3	PARL	Q9H300	518
RHBDL3	RHBDD3	Q9Y3P4	476
RHBDL3	RHBDD2	Q6NTF9	474
RHBDL3	SGSH	P51688	460
RHBDL3	VPS18	Q9P253	437
RHBDL3	HM13	Q8TCT9	426
RHBDL3	C2CD2	Q9Y426	422
RHBDL3	UBAC2	Q8NBM4	393
RHBDL3	CAPN12	Q6ZSI9	382
RHBDL3	NR3C2	P08235	381
RHBDL3	RAB11FIP4	Q86YS3	378
RHBDL3	EGFL6	Q8IUX8	377
RHBDL3	DEFB130A	P0DP74	370

IntAct

0 interactions, top by confidence:

BioGRID (5): PTCRA (Affinity Capture-Western), EIF2AK3 (Affinity Capture-Western), BIK (Affinity Capture-Western), VCP (Affinity Capture-Western), RHBDL3 (Affinity Capture-Western)

ESM2 similar proteins: A0AAS4, A2AGA4, A2AJN7, A2AWR3, F4JBM4, O14495, O42153, O82756, P20350, P58872, P58873, P70553, P97544, Q0WQX7, Q12270, Q19821, Q3SZE3, Q3TWI9, Q4JM44, Q4R763, Q4V3B8, Q53P98, Q58EK4, Q5R9A7, Q5T3F8, Q695T9, Q6NLA5, Q7T3T4, Q7TSX5, Q7Z3F1, Q810K3, Q86VZ5, Q8IWX5, Q8LF05, Q8NBS3, Q8NHU3, Q8RXW0, Q8VC82, Q8VCQ6, Q8VZ48

Diamond homologs: A2AGA4, A4WFK8, F4JBM4, O75783, O82756, O88779, P20350, P34356, P58872, P58873, Q0WQX7, Q19821, Q8VC82, Q8VZ48, Q9CAN1, Q9LYP1, Q9NX52, P54493, Q9SSR0, A0JPA1, A1AGU7, A7MGE5, A7ZSV4, A8A5N2, A9L8T6, A9MMA7, B0VX73, B1IP42, B1LI84, B1MT31, B1X769, B2U3N2, B5BHH5, B5YTX6, B6I2Y7, B7L4V0, B7LSC6, B7M2I4, B7MDQ0, B7N156

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	60
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2048 predictions. Top by Δscore:

Variant	Effect	Δscore
17:32266296:AGGAC:A	donor_gain	1.0000
17:32266297:GGAC:G	donor_gain	1.0000
17:32266297:GGACG:G	donor_gain	1.0000
17:32266298:GAC:G	donor_gain	1.0000
17:32266298:GACG:G	donor_gain	1.0000
17:32266298:GACGT:G	donor_loss	1.0000
17:32266299:AC:A	donor_gain	1.0000
17:32266299:ACGT:A	donor_loss	1.0000
17:32266300:CGT:C	donor_loss	1.0000
17:32266301:G:GG	donor_gain	1.0000
17:32284657:A:AG	acceptor_gain	1.0000
17:32284658:G:GG	acceptor_gain	1.0000
17:32284813:GCCTA:G	donor_gain	1.0000
17:32284818:G:GG	donor_gain	1.0000
17:32288786:GCACA:G	acceptor_loss	1.0000
17:32288787:CACA:C	acceptor_loss	1.0000
17:32288788:ACAG:A	acceptor_loss	1.0000
17:32288789:C:G	acceptor_gain	1.0000
17:32288789:CA:C	acceptor_loss	1.0000
17:32288790:A:AC	acceptor_loss	1.0000
17:32288791:GAT:G	acceptor_gain	1.0000
17:32288791:GATGA:G	acceptor_gain	1.0000
17:32288950:GTG:G	donor_gain	1.0000
17:32288952:G:GA	donor_gain	1.0000
17:32288965:C:G	donor_gain	1.0000
17:32289014:G:GT	donor_gain	1.0000
17:32294438:GCAGG:G	donor_gain	1.0000
17:32294441:GG:G	donor_gain	1.0000
17:32294442:GG:G	donor_gain	1.0000
17:32294442:GGTG:G	donor_loss	1.0000

AlphaMissense

2619 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:32284807:T:C	F95S	0.999
17:32298136:G:A	G238E	0.999
17:32305407:C:A	A283D	0.999
17:32321062:G:C	G350R	0.999
17:32288916:C:A	A140D	0.998
17:32288946:G:C	R150P	0.998
17:32298135:G:A	G238R	0.998
17:32298135:G:C	G238R	0.998
17:32298193:G:A	G257D	0.998
17:32305410:T:A	L284H	0.998
17:32305410:T:C	L284P	0.998
17:32305419:C:A	A287D	0.998
17:32305425:T:C	L289P	0.998
17:32320960:A:C	S316R	0.998
17:32320962:C:A	S316R	0.998
17:32320962:C:G	S316R	0.998
17:32321029:A:C	S339R	0.998
17:32321031:C:A	S339R	0.998
17:32321031:C:G	S339R	0.998
17:32321063:G:A	G350D	0.998
17:32321074:G:C	G354R	0.998
17:32288928:T:C	L144P	0.997
17:32288954:T:G	Y153D	0.997
17:32289006:C:A	T170K	0.997
17:32298135:G:T	G238W	0.997
17:32298145:T:C	L241P	0.997
17:32298192:G:C	G257R	0.997
17:32298204:G:T	G261W	0.997
17:32305397:G:T	G280W	0.997
17:32305418:G:C	A287P	0.997

dbSNP variants (sampled 300 via entrez): RS1000029421 (17:32315970 C>T), RS1000101283 (17:32316807 C>T), RS1000147363 (17:32320096 C>A,T), RS1000158746 (17:32319739 C>T), RS1000223452 (17:32279682 C>T), RS1000236313 (17:32273449 C>T), RS1000320281 (17:32301534 A>G), RS1000376061 (17:32281275 G>T), RS1000393772 (17:32313721 C>A), RS1000452179 (17:32307391 G>C), RS1000483502 (17:32267792 C>A,G,T), RS1000508116 (17:32289871 G>C), RS1000555344 (17:32266043 G>A,C), RS1000596824 (17:32279944 C>T), RS1000692893 (17:32298135 G>A)

Disease associations

OMIM: gene MIM:619017 | 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
GCST007576_165	Chronotype	5.000000e-08
GCST90014268_35	Cataracts	7.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases expression, increases methylation	4
Valproic Acid	affects expression, increases expression, increases methylation	3
entinostat	increases expression, affects cotreatment	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
lasiocarpine	increases expression	1
bisphenol A	decreases expression	1
sodium arsenite	increases expression	1
benzo(e)pyrene	decreases methylation	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Acetaminophen	increases expression	1
Carbamazepine	affects expression	1
Diethylnitrosamine	increases expression	1
Methapyrilene	decreases methylation	1
Plant Extracts	decreases expression, affects cotreatment	1
Tobacco Smoke Pollution	decreases expression	1
Aflatoxin B1	decreases methylation	1
Asbestos, Serpentine	increases methylation	1
Asbestos, Crocidolite	decreases methylation	1
Okadaic Acid	increases expression	1
Acrylamide	decreases expression	1

Clinical trials (associated diseases)

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