RHBDL1

Summary

RHBDL1 (rhomboid like 1, HGNC:10007) is a protein-coding gene on chromosome 16p13.3, encoding Rhomboid-related protein 1 (O75783). May be involved in regulated intramembrane proteolysis and the subsequent release of functional polypeptides from their membrane anchors.

This gene encodes a protein similar to Rhomboid in Drosophila which is involved in signalling in the Spitz/epidermal growth factor receptor/mitogen-activated protein kinase pathway. The Rhomboid family of proteins consists of intramembrane serine proteases containing several transmembrane domains. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 9028 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 7 total
• MANE Select transcript: NM_001278720

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10007
Approved symbol	RHBDL1
Name	rhomboid like 1
Location	16p13.3
Locus type	gene with protein product
Status	Approved
Aliases	RRP
Ensembl gene	ENSG00000103269
Ensembl biotype	protein_coding
OMIM	603264
Entrez	9028

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 9 protein_coding, 1 retained_intron

ENST00000219551, ENST00000352681, ENST00000450775, ENST00000561556, ENST00000897891, ENST00000897892, ENST00000897893, ENST00000943440, ENST00000943441, ENST00000943442

RefSeq mRNA: 3 — MANE Select: NM_001278720 NM_001278720, NM_001278721, NM_001318733

CCDS: CCDS10418, CCDS61779

Canonical transcript exons

ENST00000352681 — 8 exons

Exon	Start	End
ENSE00000664215	677639	677699
ENSE00000664216	677459	677559
ENSE00000873924	677781	678268
ENSE00001387178	675671	675829
ENSE00003555778	676971	677119
ENSE00003595717	676672	676896
ENSE00003682028	677276	677388
ENSE00003684796	676336	676497

Expression profiles

Bgee: expression breadth ubiquitous, 166 present calls, max score 95.18.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4348 / max 19.0024, expressed in 170 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
151966	0.4348	170

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	95.18	gold quality
cerebellar hemisphere	UBERON:0002245	94.24	gold quality
cerebellar cortex	UBERON:0002129	93.97	gold quality
right frontal lobe	UBERON:0002810	91.90	gold quality
cerebellum	UBERON:0002037	90.86	gold quality
cingulate cortex	UBERON:0003027	87.84	gold quality
anterior cingulate cortex	UBERON:0009835	87.76	gold quality
Brodmann (1909) area 9	UBERON:0013540	86.70	gold quality
prefrontal cortex	UBERON:0000451	85.89	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	83.81	gold quality
amygdala	UBERON:0001876	83.67	gold quality
frontal cortex	UBERON:0001870	82.50	gold quality
neocortex	UBERON:0001950	82.23	gold quality
nucleus accumbens	UBERON:0001882	81.99	gold quality
caudate nucleus	UBERON:0001873	79.95	gold quality
hypothalamus	UBERON:0001898	79.64	gold quality
adenohypophysis	UBERON:0002196	79.43	gold quality
cerebral cortex	UBERON:0000956	78.87	gold quality
putamen	UBERON:0001874	78.80	gold quality
brain	UBERON:0000955	78.16	gold quality
telencephalon	UBERON:0001893	78.01	gold quality
pituitary gland	UBERON:0000007	77.99	gold quality
mucosa of transverse colon	UBERON:0004991	77.96	gold quality
central nervous system	UBERON:0001017	77.95	gold quality
Brodmann (1909) area 10	UBERON:0013541	77.84	silver quality
forebrain	UBERON:0001890	77.78	gold quality
left adrenal gland cortex	UBERON:0035825	76.99	gold quality
apex of heart	UBERON:0002098	76.21	gold quality
right adrenal gland cortex	UBERON:0035827	75.91	gold quality
right adrenal gland	UBERON:0001233	75.75	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-CURD-114	yes	11.72
E-MTAB-6058	no	16.70
E-ANND-3	no	2.72

Regulation

Is transcription factor: no

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	rhbdl1	ENSDARG00000087040
mus_musculus	Rhbdl1	ENSMUSG00000025735
rattus_norvegicus	Rhbdl1	ENSRNOG00000019921
drosophila_melanogaster	rho-5	FBGN0041723
caenorhabditis_elegans		WBGENE00004402
caenorhabditis_elegans		WBGENE00004403

Paralogs (5): RHBDF1 (ENSG00000007384), RHBDF2 (ENSG00000129667), RHBDL3 (ENSG00000141314), RHBDL2 (ENSG00000158315), PARL (ENSG00000175193)

Protein

Protein identifiers

Rhomboid-related protein 1 — O75783 (reviewed: O75783)

Alternative names: Rhomboid-like protein 1

All UniProt accessions (2): O75783, H3BQ51

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.

Tissue specificity. Detected in heart, brain, skeletal muscle and kidney.

Similarity. Belongs to the peptidase S54 family.

Isoforms (2)

UniProt ID	Names	Canonical?
O75783-1	1	yes
O75783-2	2

RefSeq proteins (3): NP_001265649, NP_001265650, NP_001305662 (=MANE)

Domains & families (InterPro)

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

Pfam: PF01694

UniProt features (13 total): transmembrane region 7, active site 2, chain 1, splice variant 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75783-F1	72.85	0.34

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): 312 (nucleophile); 377

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 85 (showing top): MODULE_64, MODULE_66, SMID_BREAST_CANCER_LUMINAL_B_UP, MODULE_88, MODULE_11, MODULE_60, MODULE_104, CTGAGCC_MIR24, MODULE_55, GOBP_PROTEOLYSIS, NIKOLSKY_BREAST_CANCER_16P13_AMPLICON, MODULE_13, GOMF_PEPTIDASE_ACTIVITY, MORF_TNFRSF25, MODULE_23

GO Biological Process (2): proteolysis (GO:0006508), signal transduction (GO:0007165)

GO Molecular Function (5): 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 (2): plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein metabolic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
endopeptidase activity	1
serine-type peptidase activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
serine hydrolase activity	1
catalytic activity	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

794 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RHBDL1	RHBDD1	Q8TEB9	724
RHBDL1	A0A1W2PP11	A0A1W2PP11	687
RHBDL1	PARL	Q9H300	687
RHBDL1	RHBDF1	Q96CC6	621
RHBDL1	RHBDF2	Q6PJF5	596
RHBDL1	RHBDD2	Q6NTF9	587
RHBDL1	RHBDD3	Q9Y3P4	556
RHBDL1	UBAC2	Q8NBM4	485
RHBDL1	EGFR	P00533	474
RHBDL1	TTLL2	Q9BWV7	469
RHBDL1	OR10S1	Q8NGN2	434
RHBDL1	TTLL3	Q9Y4R7	423
RHBDL1	WDR90	Q96KV7	422
RHBDL1	CLEC14A	Q86T13	415
RHBDL1	TM7SF2	O76062	402

IntAct

39 interactions, top by confidence:

A	B	Type	Score
RHBDL1	KRTAP2-4	psi-mi:“MI:0915”(physical association)	0.560
KRTAP6-3	RHBDL1	psi-mi:“MI:0915”(physical association)	0.560
RHBDL1	VAC14	psi-mi:“MI:0915”(physical association)	0.560
TUSC5	RHBDL1	psi-mi:“MI:0915”(physical association)	0.560
RHBDL1	ARLN	psi-mi:“MI:0915”(physical association)	0.560
RHBDL1	KRTAP10-8	psi-mi:“MI:0915”(physical association)	0.560
RHBDL1	SPTSSA	psi-mi:“MI:0915”(physical association)	0.560
RHBDL1	ABHD16A	psi-mi:“MI:0915”(physical association)	0.560
RHBDL1	COMT	psi-mi:“MI:0915”(physical association)	0.560
RHBDL1	FXYD6	psi-mi:“MI:0915”(physical association)	0.560
RHBDL1	APOD	psi-mi:“MI:0915”(physical association)	0.560
RHBDL1	MFF	psi-mi:“MI:0915”(physical association)	0.560
RHBDL1	ITGB8	psi-mi:“MI:0914”(association)	0.530
RHBDL1	KRTAP2-4	psi-mi:“MI:0915”(physical association)	0.000
RHBDL1	KRTAP6-3	psi-mi:“MI:0915”(physical association)	0.000
RHBDL1	VAC14	psi-mi:“MI:0915”(physical association)	0.000
TUSC5	RHBDL1	psi-mi:“MI:0915”(physical association)	0.000
APOD	RHBDL1	psi-mi:“MI:0915”(physical association)	0.000
ARLN	RHBDL1	psi-mi:“MI:0915”(physical association)	0.000
RHBDL1	KRTAP10-8	psi-mi:“MI:0915”(physical association)	0.000
SPTSSA	RHBDL1	psi-mi:“MI:0915”(physical association)	0.000
ABHD16A	RHBDL1	psi-mi:“MI:0915”(physical association)	0.000
COMT	RHBDL1	psi-mi:“MI:0915”(physical association)	0.000
FXYD6	RHBDL1	psi-mi:“MI:0915”(physical association)	0.000
MFF	RHBDL1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (24): MAGI3 (Affinity Capture-MS), DLG3 (Affinity Capture-MS), HERC3 (Affinity Capture-MS), MAGI3 (Affinity Capture-MS), DLG3 (Affinity Capture-MS), MAGI2 (Affinity Capture-MS), ITGB8 (Affinity Capture-MS), RHBDL1 (Two-hybrid), RHBDL1 (Two-hybrid), FXYD6 (Two-hybrid), C4orf3 (Two-hybrid), SPTSSA (Two-hybrid), MFF (Two-hybrid), TUSC5 (Two-hybrid), KRTAP10-8 (Two-hybrid)

ESM2 similar proteins: A0JP80, A1A5Z0, A5D6W6, A7YWN2, B2MVP8, B6CZ46, L5KLU7, O42153, O75783, O75908, O77759, O88908, P58872, P58873, P86243, Q1HG44, Q1KZG0, Q1XHX8, Q32LM8, Q49LS7, Q52KL1, Q5CZN0, Q5KR61, Q5T197, Q5TM67, Q5XIL6, Q6AX73, Q6AZ83, Q6MG14, Q6NSQ9, Q6P5W5, Q767L9, Q7TNJ2, Q7TQM4, Q80YU0, Q86VD9, Q8AVI9, Q8CIP5, Q8IWX5, Q8IXM6

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

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

1383 predictions. Top by Δscore:

Variant	Effect	Δscore
16:676965:CCCCA:C	acceptor_loss	1.0000
16:676966:CCCAG:C	acceptor_loss	1.0000
16:676967:CCA:C	acceptor_loss	1.0000
16:676968:CAGAT:C	acceptor_loss	1.0000
16:676969:A:AG	acceptor_gain	1.0000
16:676970:G:GA	acceptor_loss	1.0000
16:676970:G:GG	acceptor_gain	1.0000
16:676970:GATC:G	acceptor_gain	1.0000
16:676991:C:CA	acceptor_gain	1.0000
16:676992:G:A	acceptor_gain	1.0000
16:677115:GTTGG:G	donor_gain	1.0000
16:677116:TTGG:T	donor_gain	1.0000
16:677117:TGG:T	donor_gain	1.0000
16:677118:GG:G	donor_gain	1.0000
16:677118:GGG:G	donor_gain	1.0000
16:677119:GG:G	donor_gain	1.0000
16:677119:GGTG:G	donor_loss	1.0000
16:677120:G:GG	donor_gain	1.0000
16:677121:T:G	donor_loss	1.0000
16:677123:AGTAG:A	donor_loss	1.0000
16:677259:T:TA	acceptor_gain	1.0000
16:677267:T:A	acceptor_gain	1.0000
16:677269:T:TA	acceptor_gain	1.0000
16:677270:G:A	acceptor_gain	1.0000
16:677274:A:AG	acceptor_gain	1.0000
16:677274:AG:A	acceptor_gain	1.0000
16:677274:AGGCT:A	acceptor_gain	1.0000
16:677275:G:A	acceptor_loss	1.0000
16:677275:G:GT	acceptor_gain	1.0000
16:677275:GG:G	acceptor_gain	1.0000

AlphaMissense

2406 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:676980:T:C	F211L	0.999
16:676982:C:A	F211L	0.999
16:676982:C:G	F211L	0.999
16:677320:G:A	G272E	0.999
16:677515:G:T	G314W	0.999
16:677525:C:A	A317D	0.999
16:677543:T:C	L323P	0.999
16:677783:A:C	S350R	0.999
16:677785:C:A	S350R	0.999
16:677785:C:G	S350R	0.999
16:677795:G:C	G354R	0.999
16:677796:G:A	G354D	0.999
16:677852:A:C	S373R	0.999
16:677854:C:A	S373R	0.999
16:677854:C:G	S373R	0.999
16:677874:G:A	G380D	0.999
16:677885:G:A	G384R	0.999
16:677885:G:C	G384R	0.999
16:677885:G:T	G384W	0.999
16:677886:G:A	G384E	0.999
16:677891:A:C	S386R	0.999
16:677893:C:A	S386R	0.999
16:677893:C:G	S386R	0.999
16:677897:G:C	G388R	0.999
16:677058:T:G	Y237D	0.998
16:677329:T:C	L275P	0.998
16:677376:G:C	G291R	0.998
16:677377:G:A	G291D	0.998
16:677465:T:C	L297P	0.998
16:677503:G:A	G310R	0.998

dbSNP variants (sampled 300 via entrez): RS1000019896 (16:675919 G>A), RS1000246681 (16:675286 C>T), RS1000456455 (16:675529 G>T), RS1001041769 (16:674739 C>T), RS1001430399 (16:674854 A>G), RS1001490677 (16:675292 G>A,C,T), RS1002185589 (16:676074 T>C,G), RS1002391688 (16:678756 G>A), RS1002496699 (16:674496 C>G,T), RS1002829648 (16:678503 G>A,T), RS1002952596 (16:678228 T>A), RS1003122039 (16:674601 G>A), RS1003803520 (16:677828 C>A), RS1004170281 (16:674127 T>C), RS1004333114 (16:678325 G>A)

Disease associations

OMIM: gene MIM:603264 | disease phenotypes: MIM:618093

GenCC curated gene-disease

Mondo (1): spinocerebellar ataxia 48 (MONDO:0032526)

Orphanet (1): Spinocerebellar ataxia type 48 (Orphanet:631103)

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST005951_12	Body mass index	5.000000e-11
GCST010796_5294	Electrocardiogram morphology (amplitude at temporal datapoints)	9.000000e-09
GCST010796_5295	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-08
GCST010796_5296	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-08
GCST010796_5297	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004327	electrocardiography

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	affects expression, increases abundance, increases expression	2
aristolochic acid I	increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	decreases expression	1
arsenite	affects binding, decreases reaction	1
sulforaphane	increases expression	1
sodium arsenite	decreases expression	1
Sunitinib	increases expression	1
Benzo(a)pyrene	increases methylation	1
Estradiol	affects cotreatment, decreases expression	1
Lead	affects expression	1
Ozone	affects expression, increases abundance	1
Smoke	increases expression, increases abundance	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1
Sodium Selenite	increases expression	1
Okadaic Acid	decreases expression	1
Acrylamide	decreases expression	1

Clinical trials (associated diseases)

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