CIROP

Summary

CIROP (ciliated left-right organizer metallopeptidase, HGNC:53647) is a protein-coding gene on chromosome 14q11.2, encoding Ciliated left-right organizer metallopeptidase (A0A1B0GTW7). Putative metalloproteinase that plays a role in left-right patterning process.

Predicted to enable peptidase activity. Predicted to be involved in establishment of left/right asymmetry. Predicted to be located in membrane. Predicted to be active in cytoplasm. Implicated in visceral heterotaxy 12.

Source: NCBI Gene 100128908 — RefSeq curated summary.

At a glance

• Gene–disease (curated): visceral heterotaxy (Strong, GenCC)
• Clinical variants (ClinVar): 19 total — 6 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 28
• MANE Select transcript: NM_001354640

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:53647
Approved symbol	CIROP
Name	ciliated left-right organizer metallopeptidase
Location	14q11.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000283654
Ensembl biotype	protein_coding
OMIM	619703
Entrez	100128908

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 retained_intron

ENST00000637218, ENST00000642668, ENST00000644000, ENST00000644147, ENST00000940842

RefSeq mRNA: 2 — MANE Select: NM_001354640 NM_001354640, NM_001402427

CCDS: CCDS86373

Canonical transcript exons

ENST00000637218 — 16 exons

Exon	Start	End
ENSE00003792107	23101842	23101911
ENSE00003792917	23104243	23104294
ENSE00003794261	23102092	23102266
ENSE00003794498	23100850	23101079
ENSE00003794798	23100502	23100681
ENSE00003795688	23104599	23104989
ENSE00003795735	23103287	23103382
ENSE00003796492	23104385	23104469
ENSE00003798412	23101292	23101564
ENSE00003798427	23103675	23103818
ENSE00003798922	23102629	23102713
ENSE00003799420	23101669	23101765
ENSE00003799482	23099062	23099489
ENSE00003800035	23102926	23103051
ENSE00003800542	23103471	23103548
ENSE00003800912	23102344	23102489

Expression profiles

Bgee: expression breadth broad, 49 present calls, max score 51.23.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1182 / max 114.3779, expressed in 29 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
142312	0.0496	15
142309	0.0229	3
142310	0.0206	5
142314	0.0116	2
142313	0.0103	6
142311	0.0032	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of stomach	UBERON:0001199	51.23	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	51.17	gold quality
primary visual cortex	UBERON:0002436	48.24	gold quality
substantia nigra	UBERON:0002038	47.78	gold quality
left lobe of thyroid gland	UBERON:0001120	46.28	gold quality
thyroid gland	UBERON:0002046	45.99	gold quality
right lobe of thyroid gland	UBERON:0001119	44.79	gold quality
prefrontal cortex	UBERON:0000451	43.02	gold quality
granulocyte	CL:0000094	42.71	silver quality
Brodmann (1909) area 9	UBERON:0013540	42.11	gold quality
urinary bladder	UBERON:0001255	41.70	silver quality
colonic epithelium	UBERON:0000397	41.32	gold quality
frontal cortex	UBERON:0001870	40.78	gold quality
sural nerve	UBERON:0015488	40.68	gold quality
ventricular zone	UBERON:0003053	40.03	gold quality
lymph node	UBERON:0000029	39.98	gold quality
cortical plate	UBERON:0005343	39.94	gold quality
stromal cell of endometrium	CL:0002255	39.57	gold quality
superior frontal gyrus	UBERON:0002661	39.50	gold quality
muscle layer of sigmoid colon	UBERON:0035805	39.20	gold quality
Ammon’s horn	UBERON:0001954	39.10	silver quality
ganglionic eminence	UBERON:0004023	39.08	gold quality
lower esophagus muscularis layer	UBERON:0035833	39.02	silver quality
lower esophagus	UBERON:0013473	38.94	silver quality
putamen	UBERON:0001874	38.83	gold quality
colon	UBERON:0001155	38.36	gold quality
smooth muscle tissue	UBERON:0001135	38.30	gold quality
cerebral cortex	UBERON:0000956	38.29	gold quality
intestine	UBERON:0000160	38.04	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	37.88	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.29

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 1)

• Discovery of a genetic module essential for assigning left-right asymmetry in humans and ancestral vertebrates. (PMID:34903892)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cirop	ENSDARG00000098915
mus_musculus	Cirop	ENSMUSG00000114865
rattus_norvegicus	Cirop	ENSRNOG00000057827

Protein

Protein identifiers

Ciliated left-right organizer metallopeptidase — A0A1B0GTW7 (reviewed: A0A1B0GTW7)

Alternative names: Leishmanolysin-like peptidase 2

All UniProt accessions (2): A0A1B0GTW7, A0A2R8Y752

UniProt curated annotations — full annotation on UniProt →

Function. Putative metalloproteinase that plays a role in left-right patterning process.

Subcellular location. Membrane.

Disease relevance. Heterotaxy, visceral, 12, autosomal (HTX12) [MIM:619702] A form of visceral heterotaxy, a complex disorder due to disruption of the normal left-right asymmetry of the thoracoabdominal organs. Visceral heterotaxy or situs ambiguus results in randomization of the placement of visceral organs, including the heart, lungs, liver, spleen, and stomach. The organs are oriented randomly with respect to the left-right axis and with respect to one another. It can be associated with a variety of congenital defects including cardiac malformations. Early death may occur. HTX12 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 zinc ion per subunit.

Similarity. Belongs to the peptidase M8 family.

Isoforms (3)

UniProt ID	Names	Canonical?
A0A1B0GTW7-1	1	yes
A0A1B0GTW7-2	2
A0A1B0GTW7-3	3

RefSeq proteins (2): NP_001341569, NP_001389356 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001577	Peptidase_M8	Family

Pfam: PF01457

UniProt features (31 total): sequence variant 8, glycosylation site 5, splice variant 4, binding site 3, topological domain 2, sequence conflict 2, region of interest 2, signal peptide 1, chain 1, transmembrane region 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A0A1B0GTW7-F1	73.73	0.35

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 (1): 306

Ligand- & substrate-binding residues (3): 309; 385; 305

Glycosylation sites (5): 333, 425, 491, 524, 713

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 64 (showing top): GOMF_METALLOPEPTIDASE_ACTIVITY, GOBP_SPECIFICATION_OF_SYMMETRY, GOBP_PROTEOLYSIS, GOMF_PEPTIDASE_ACTIVITY, ZBTB18_TARGET_GENES, HP_PULMONIC_STENOSIS, HP_PATENT_DUCTUS_ARTERIOSUS, HP_PATENT_FORAMEN_OVALE, HP_TRANSPOSITION_OF_THE_GREAT_ARTERIES, HP_ABNORMAL_CARDIAC_SEPTUM_MORPHOLOGY, HP_COMPLETE_ATRIOVENTRICULAR_CANAL_DEFECT, HP_ABNORMAL_AORTIC_MORPHOLOGY, HP_COARCTATION_OF_AORTA, HP_ABNORMAL_CARDIAC_VENTRICLE_MORPHOLOGY, HP_SINGLE_VENTRICLE

GO Biological Process (3): proteolysis (GO:0006508), cell adhesion (GO:0007155), establishment of left/right asymmetry (GO:0061966)

GO Molecular Function (5): metalloendopeptidase activity (GO:0004222), peptidase activity (GO:0008233), metal ion binding (GO:0046872), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787)

GO Cellular Component (2): cytoplasm (GO:0005737), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
protein metabolic process	1
cellular process	1
determination of left/right symmetry	1
endopeptidase activity	1
metallopeptidase activity	1
hydrolase activity	1
catalytic activity, acting on a protein	1
cation binding	1
peptidase activity	1
catalytic activity	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

128 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CIROP	GPR65	Q8IYL9	285
CIROP	MAPK15	Q8TD08	283
CIROP	DRC9	Q9H095	243
CIROP	DPP3	Q9NY33	243
CIROP	PREPL	Q4J6C6	213
CIROP	PREP	P48147	213
CIROP	FLCN	Q8NFG4	207
CIROP	DDIT4	Q9NX09	205
CIROP	ATG13	O75143	205
CIROP	PSEN1	P49768	186
CIROP	PSEN2	P49810	186
CIROP	MIPEP	Q99797	183
CIROP	GPR68	Q15743	183
CIROP	LGMN	Q99538	180
CIROP	MMS19	Q96T76	170

IntAct

0 interactions, top by confidence:

ESM2 similar proteins: A0A1B0GTW7, A0A1D5NSK0, A0A1L8HYT7, A0A286YEC0, D3ZT86, D3ZWJ9, D4A929, F8W3R9, G7PWZ3, I6M4H4, O08852, O43157, O43278, O75074, O88204, P17813, P49000, P59383, Q04912, Q17R55, Q499Z3, Q4R3B7, Q4TUC0, Q5ND34, Q62190, Q63961, Q6AXX1, Q76MJ5, Q7TN88, Q7TQH7, Q7Z442, Q7Z4F1, Q80W87, Q80YN4, Q866Y3, Q86VZ4, Q8BHW9, Q8BMN4, Q8BYI8, Q8BZT7

Diamond homologs: A0A1B0GTW7, A0A1D5NSK0, A0A1L8HYT7, A0A286YEC0, O62446, Q29AK2, Q61YG1, Q8BMN4, Q9VH19, Q96KR4

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	2
Uncertain significance	3
Likely benign	6
Benign	0

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
1335922	NM_001354640.2(CIROP):c.1364TCT[1] (p.Phe456del)	Pathogenic
1344488	NM_001354640.2(CIROP):c.1151C>T (p.Ser384Leu)	Pathogenic
1344490	NM_001354640.2(CIROP):c.1037G>A (p.Trp346Ter)	Pathogenic
1344493	NM_001354640.2(CIROP):c.1166G>T (p.Arg389Ile)	Pathogenic
1344495	NM_001354640.2(CIROP):c.571C>T (p.Arg191Ter)	Pathogenic
3390959	NM_001354640.2(CIROP):c.988+1G>C	Pathogenic
1804116	NM_001354640.2(CIROP):c.1331dup (p.Leu444fs)	Likely pathogenic
4277705	NM_001354640.2(CIROP):c.1126G>A (p.Glu376Lys)	Likely pathogenic

SpliceAI

3 predictions. Top by Δscore:

Variant	Effect	Δscore
14:23099576:T:A	acceptor_gain	0.4000
14:23099578:G:C	acceptor_gain	0.3900
14:23099198:T:TG	donor_gain	0.2200

AlphaMissense

5032 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:23102654:C:A	W321C	0.992
14:23102654:C:G	W321C	0.992
14:23102099:C:A	W434C	0.989
14:23102099:C:G	W434C	0.989
14:23102678:G:C	F313L	0.987
14:23102678:G:T	F313L	0.987
14:23102680:A:G	F313L	0.987
14:23102243:C:A	W386C	0.986
14:23102243:C:G	W386C	0.986
14:23102138:C:A	W421C	0.985
14:23102138:C:G	W421C	0.985
14:23102140:A:G	W421R	0.984
14:23102140:A:T	W421R	0.984
14:23101557:C:G	C495S	0.983
14:23101558:A:T	C495S	0.983
14:23102656:A:G	W321R	0.982
14:23102656:A:T	W321R	0.982
14:23101895:A:C	F442L	0.981
14:23101895:A:T	F442L	0.981
14:23101897:A:G	F442L	0.981
14:23104292:C:G	C137S	0.981
14:23104293:A:T	C137S	0.981
14:23101724:C:G	C474S	0.979
14:23101725:A:T	C474S	0.979
14:23101482:C:G	C520S	0.978
14:23101483:A:T	C520S	0.978
14:23101754:C:G	C464S	0.976
14:23101755:A:T	C464S	0.976
14:23101851:C:G	C457S	0.976
14:23101852:A:T	C457S	0.976

dbSNP variants (sampled 300 via entrez): RS1000331254 (14:23106182 G>A,C,T), RS1000481124 (14:23102761 T>A,C), RS1001213501 (14:23102780 C>A,T), RS1002890563 (14:23104181 T>C), RS1003172037 (14:23105196 G>T), RS1003229032 (14:23099757 T>C), RS1003260258 (14:23099609 G>A,T), RS1003332411 (14:23099394 C>G,T), RS1003928040 (14:23102382 C>A,T), RS1004137213 (14:23099548 C>T), RS1004360386 (14:23104302 A>C), RS1004519991 (14:23099603 A>G), RS1004570905 (14:23099867 T>C), RS1004858412 (14:23104458 G>A,C), RS1005099373 (14:23105566 C>A,T)

Disease associations

OMIM: gene MIM:619703 | disease phenotypes: MIM:619702, MIM:601675

GenCC curated gene-disease

Disease	Classification	Inheritance
visceral heterotaxy	Strong	Autosomal recessive

Mondo (3): heterotaxy, visceral, 12, autosomal (MONDO:0859222), trichothiodystrophy 1, photosensitive (MONDO:0011125), visceral heterotaxy (MONDO:0018677)

Orphanet (2): Trichothiodystrophy (Orphanet:33364), PIBIDS syndrome (Orphanet:670)

HPO phenotypes

28 total (28 of 28 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001629	Ventricular septal defect
HP:0001631	Atrial septal defect
HP:0001642	Pulmonic stenosis
HP:0001643	Patent ductus arteriosus
HP:0001651	Dextrocardia
HP:0001655	Patent foramen ovale
HP:0001674	Complete atrioventricular canal defect
HP:0001680	Coarctation of aorta
HP:0001696	Situs inversus totalis
HP:0001719	Double outlet right ventricle
HP:0001750	Single ventricle
HP:0003577	Congenital onset
HP:0004383	Hypoplastic left ventricle
HP:0004935	Pulmonary artery atresia
HP:0010773	Partial anomalous pulmonary venous return
HP:0011540	Levotransposition of the great arteries
HP:0011553	Discordant atrioventricular connection
HP:0011556	Double inlet right ventricle
HP:0011565	Common atrium
HP:0011590	Double aortic arch
HP:0011640	Single coronary artery origin
HP:0011670	Left superior vena cava draining to coronary sinus
HP:0012020	Right aortic arch
HP:0012304	Hypoplastic aortic arch
HP:0031348	Dextrotransposition of the great arteries
HP:0031565	Abdominal situs ambiguus
HP:0031854	Left Isomerism

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

1 total (human), top 1 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01591928	Not specified	COMPLETED	Heterotaxy Syndrome and Intestinal Rotation Abnormalities - A Prospective Study
NCT01929967	Not specified	COMPLETED	Defining Immunodeficiency in Heterotaxy Syndrome: Pilot Study Data
NCT02432079	Not specified	RECRUITING	Molecular Genetics of Heterotaxy and Related Congenital Heart Defects