OTC

Summary

OTC (ornithine transcarbamylase, HGNC:8512) is a protein-coding gene on chromosome Xp11.4, encoding Ornithine transcarbamylase, mitochondrial (P00480). Catalyzes the second step of the urea cycle, the condensation of carbamoyl phosphate with L-ornithine to form L-citrulline. It is haploinsufficient (ClinGen: sufficient evidence).

This nuclear gene encodes a mitochondrial matrix enzyme. The encoded protein is involved in the urea cycle which functions to detoxify ammonia into urea for excretion. Mutations in this enzyme lead to ornithine transcarbamylase deficiency, which causes hyperammonemia.

Source: NCBI Gene 5009 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ornithine carbamoyltransferase deficiency (Definitive, ClinGen)
• Clinical variants (ClinVar): 1,027 total — 327 pathogenic, 107 likely-pathogenic
• Phenotypes (HPO): 51
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000531

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8512
Approved symbol	OTC
Name	ornithine transcarbamylase
Location	Xp11.4
Locus type	gene with protein product
Status	Approved
Aliases	OTCase, OTCD, OTC1
Ensembl gene	ENSG00000036473
Ensembl biotype	protein_coding
OMIM	300461
Entrez	5009

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 12 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000039007, ENST00000488812, ENST00000643344, ENST00000713758, ENST00000713759, ENST00000713760, ENST00000909233, ENST00000909234, ENST00000909235, ENST00000909236, ENST00000909237, ENST00000909238, ENST00000909239, ENST00000909240, ENST00000909241

RefSeq mRNA: 2 — MANE Select: NM_000531 NM_000531, NM_001407092

CCDS: CCDS14247

Canonical transcript exons

ENST00000039007 — 10 exons

Exon	Start	End
ENSE00000668290	38408876	38409025
ENSE00000668292	38411862	38411999
ENSE00001090980	38381342	38381429
ENSE00001090983	38369796	38369877
ENSE00003560546	38401275	38401428
ENSE00003605466	38408742	38408795
ENSE00003606244	38367291	38367429
ENSE00003638371	38403618	38403740
ENSE00004021164	38421023	38421446
ENSE00004021168	38352604	38352773

Expression profiles

Bgee: expression breadth ubiquitous, 139 present calls, max score 95.49.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.7305 / max 284.4917, expressed in 43 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
195935	0.6157	34
195934	0.0720	20
209654	0.0269	10
195936	0.0159	11

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	95.49	gold quality
right lobe of liver	UBERON:0001114	95.12	gold quality
liver	UBERON:0002107	93.33	gold quality
duodenum	UBERON:0002114	93.06	gold quality
mucosa of transverse colon	UBERON:0004991	85.49	gold quality
ileal mucosa	UBERON:0000331	81.95	gold quality
small intestine	UBERON:0002108	81.11	gold quality
small intestine Peyer’s patch	UBERON:0003454	80.65	gold quality
jejunum	UBERON:0002115	76.53	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	74.81	silver quality
rectum	UBERON:0001052	69.46	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	65.37	gold quality
transverse colon	UBERON:0001157	62.33	gold quality
right coronary artery	UBERON:0001625	61.87	gold quality
intestine	UBERON:0000160	61.30	gold quality
pancreatic ductal cell	CL:0002079	61.12	silver quality
diaphragm	UBERON:0001103	61.09	gold quality
islet of Langerhans	UBERON:0000006	59.71	gold quality
body of pancreas	UBERON:0001150	59.28	gold quality
pancreas	UBERON:0001264	58.84	gold quality
smooth muscle tissue	UBERON:0001135	57.00	gold quality
gall bladder	UBERON:0002110	56.55	gold quality
vermiform appendix	UBERON:0001154	55.95	gold quality
caecum	UBERON:0001153	54.76	gold quality
endometrium epithelium	UBERON:0004811	54.76	gold quality
large intestine	UBERON:0000059	54.29	gold quality
colon	UBERON:0001155	54.22	gold quality
right lung	UBERON:0002167	53.62	gold quality
left uterine tube	UBERON:0001303	53.20	gold quality
cerebellar vermis	UBERON:0004720	53.18	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	18.00
E-ANND-3	yes	4.34

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPB, HNF4A, NCOA1, PPARGC1A

miRNA regulators (miRDB)

35 targeting OTC, 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-450A-1-3P	100.00	69.33	1837
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-4517	99.76	69.19	1867
HSA-MIR-379-3P	99.69	69.60	1524
HSA-MIR-411-3P	99.69	69.63	1524
HSA-MIR-5197-5P	99.64	69.08	1494
HSA-MIR-3616-5P	99.55	67.02	989
HSA-MIR-573	99.55	67.44	955
HSA-MIR-578	99.46	68.36	1787
HSA-MIR-653-5P	99.46	67.35	1300
HSA-MIR-942-5P	99.41	68.40	1977
HSA-MIR-889-3P	99.40	69.76	2103
HSA-MIR-103A-1-5P	99.39	67.78	1545
HSA-MIR-103A-2-5P	99.39	67.72	1577
HSA-MIR-135A-5P	99.36	71.85	1601
HSA-MIR-135B-5P	99.36	71.63	1613
HSA-MIR-4652-3P	99.33	70.02	2742
HSA-MIR-190B-3P	99.33	68.29	1382
HSA-MIR-5583-3P	99.06	65.68	1018
HSA-MIR-16-1-3P	98.70	69.23	1538
HSA-MIR-548AO-5P	98.55	69.57	1362
HSA-MIR-548AX	98.55	69.58	1362
HSA-MIR-6792-5P	98.39	68.16	1330
HSA-MIR-1262	98.17	66.52	757
HSA-MIR-4701-3P	98.17	66.25	788

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• deficiency in ornithine carbamoyltransferase enzymatic function conferred by the R40H mutation is likely caused by enhanced degradation of the preprotein in the cytosol. (PMID:11768581)
• ornithine transcarbamylase (OTC) deficiency: review of mutations and polymorphisms in the human ornithine transcarbamylase gene (PMID:11793468)
• seven novel missense mutations, two splice-site mutations, two microdeletions and a polymorphic amino acid substitution in the gene for ornithine transcarbamylase (OTC) in patients with OTC deficiency (PMID:11793483)
• novel mutations in the ornithine transcarbamylase gene (PMID:12083811)
• Haplotype analysis and phylogeny of polymorphisms of this protein were studied in two male populations. (PMID:12516615)
• Using 2 (CA)n flanking markers of the OTC gene (DXS997 & DXS1068), the haplotypic background of 37 different mutational events was defined & compared with random control chromosomes. 1 particular haplotype is a risk factor for carrying OTC mutations. (PMID:15300856)
• Mutations in the human ornithine transcarbamylase (OTC) gene is detected in patients with Hyperammonemia-induced encephalopathy due to ornithine transcarbamylase deficiency. (PMID:15692798)
• Novel mutations within the OTC gene are associated with Ornithine transcarbamylase (OTC) deficiency disorder. (PMID:16786505)
• Novel mutations p.Leu9X, p.Arg26Pro, p.Gly100Arg, p.Met205Thr, p.Lys221Asn, p.Asp249Gly, p.Phe281Ser, p.Val323Met, c.571delC, c.853delC, and c.796-805del are associated with OTC deficiency. (PMID:17041896)
• Describe a contiguous gene syndrome involving the RPGR, OTC and TM4SF2 genes in a male patient with severe neonatal ornithine transcarbamylase deficiency. (PMID:17570074)
• Data show that OCT/ALT is a potent indicator for the diagnosis and the prognosis of hepatocellular carcinoma. (PMID:17570354)
• our results suggest the involvement of a new pathway in AD brains involving the urea cycle. (PMID:17893704)
• In ten families with late-onset ornithine transcarbamylase (OTC) deficiency in male patients, three mutant alleles-R40H, R277W, and Y55D-were identified. (PMID:18030415)
• Two known and three novel mutations of the ornithine transcarbamylase (OTC) gene are reported in five Japanese patients with OTC deficieny including two neonatal-onset, one late-onset, and two symptomatic female patients. (PMID:18204299)
• The rs5963409 minor allele was weakly but significantly associated with an increased risk of developing AD. (PMID:18983895)
• Deletions and gene rearrangements of OTC gene are associated with Ornithine Carbamoyltransferase Deficiency Disease. (PMID:19138872)
• Hypocitrullinemia in expanded newborn screening is not a reliable marker for OTCD. (PMID:19359120)
• the identification of novel disease-causing mutations in Ornithine transcarbamylase deficiency and increases the knowledge on possible mutational mechanisms generating deletions in ornithine transcaramylase. (PMID:19475717)
• OTC rs5963409 polymorphism may be associated with hypertension and coronary vasomotion in males (PMID:19574962)
• These results indicate that mutant alleles with late-onset OCT deficiency syndrome have recurrently arisen, have been retained in some populations, and some appear to hvae a common ancestor. (PMID:19893582)
• Mutations in the regulatory regions of OTC can lead to ornithine carbamoyltransferase deficiency and should be included in genetic testing. (PMID:20127982)
• In patients with a clinical and biochemical presentation of OTCD and negative OTC sequencing, whole genome or targeted chromosomal microarray analysis (CMA) with coverage of the OTC and neighboring genes should be performed as a reflex test. (PMID:20817516)
• carriers of the ornithine transcarbamylase (OTC) mutation are at risk for developing hyperammonemia coma during the postpartum period and at times of metabolic stress. (PMID:21956151)
• V339G and W332S mutations of OTC have been discovered for the first time (PMID:24711021)
• Ornithine transcarbamylase deficiency was genetically heterogeneous in seven Korean patients with confirmed ornithine transcarbamylase deficiency diagnosis by biochemical findings and/or genetic analysis, together with two novel mutations in the OTC gene (PMID:25011434)
• aim of this study was to provide clues for recognition of OTCD in adults and analyze the environmental factors that, interacting with OTC gene mutations, might have triggered acute clinical manifestations (PMID:25026867)
• HNF-4alpha most likely plays an essential role in the initiation of OTC transcription in human. (PMID:25056436)
• Data indicate that all of the three patients have carried ornithine transcarbamylase gene mutations, patients 1 and 2 were both hemizygous for mutation c.586G> A(p.D196N). (PMID:25297582)
• The corresponding OTC tissue enzyme activities were between 3-6% of normal control in mouse and human liver. The use of the cryptic splice sites was reproduced in minigenes carrying murine or human mutant sequences (PMID:25853564)
• In Korean patients with OTC deficiency, mutations in OTC are genetically heterogeneous. (PMID:25994866)
• OTC mutation and phenotype in ornithine transcarbamylase deficiency (PMID:26059767)
• Sanger sequencing of the ornithine transcarbamylase (OTC) gene revealed a novel hemizygous deletion at the fourth nucleotide of intron 4 (c.386+4delT) in a child with hyperammonemia and his asymptomatic mother. (PMID:26446336)
• Low expression of OTC is associated with glioblastoma. (PMID:27431689)
• The measurement of serum ornithine carbamoyltransferase concentration may provide a useful marker of disease severity, and thus could be a useful marker for a high risk of hepatocellular carcinoma occurrence. (PMID:28824294)
• In nine of 38 subjects (24%) with OTC deficiency, this study identified a sequence variant in the OTC regulatory regions. (PMID:29282796)
• indicate that the proportion of about 20-30% of hepatocytes expressing the functional OTC protein is not sufficient to maintain metabolic stability. X-inactivation ratios assessed in liver biopsies taken from heterozygous females with X-linked disorders should not be considered representative of the whole liver (PMID:29623395)
• Whole exome sequencing successfully identified disease-causing mutations including two novel ones: the c.209_210delAA (p.Lys70Argfs*17) and the c.850T>A (p.Tyr284Asn). (PMID:30223008)
• Generation of an induced pluripotent stem cell line (SDQLCHi009-A) from a patient with 47,XXY and ornithine transcarbamylase deficiency carrying a hemizygote mutation in OTC. (PMID:32014801)
• Neonatal factors related to survival and intellectual and developmental outcome of patients with early-onset urea cycle disorders. (PMID:32273051)
• Clinical and genetic analysis of five Chinese patients with urea cycle disorders. (PMID:32410394)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	otc	ENSDARG00000062147
mus_musculus	Otc	ENSMUSG00000031173
rattus_norvegicus	Otc	ENSRNOG00000003370

Paralogs (2): CPS1 (ENSG00000021826), CAD (ENSG00000084774)

Protein

Protein identifiers

Ornithine transcarbamylase, mitochondrial — P00480 (reviewed: P00480)

Alternative names: Ornithine carbamoyltransferase, mitochondrial

All UniProt accessions (4): A0A2R8Y829, A0AAQ5BGS9, A0AAQ5BGV3, P00480

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the second step of the urea cycle, the condensation of carbamoyl phosphate with L-ornithine to form L-citrulline. The urea cycle ensures the detoxification of ammonia by converting it to urea for excretion.

Subunit / interactions. Homotrimer.

Subcellular location. Mitochondrion matrix.

Tissue specificity. Mainly expressed in liver and intestinal mucosa.

Post-translational modifications. Acetylation at Lys-88 negatively regulates ornithine carbamoyltransferase activity in response to nutrient signals.

Disease relevance. Ornithine carbamoyltransferase deficiency (OTCD) [MIM:311250] An X-linked disorder of the urea cycle which causes a form of hyperammonemia. Mutations with no residual enzyme activity are always expressed in hemizygote males by a very severe neonatal hyperammonemic coma that generally proves to be fatal. Heterozygous females are either asymptomatic or express orotic aciduria spontaneously or after protein intake. The disorder is treatable with supplemental dietary arginine and low protein diet. The arbitrary classification of patients into the ’neonatal’ group (clinical hyperammonemia in the first few days of life) and ’late’ onset (clinical presentation after the neonatal period) has been used to differentiate severe from mild forms. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Negatively regulated by lysine acetylation.

Pathway. Nitrogen metabolism; urea cycle; L-citrulline from L-ornithine and carbamoyl phosphate: step 1/1.

Similarity. Belongs to the aspartate/ornithine carbamoyltransferase superfamily. OTCase family.

RefSeq proteins (2): NP_000522, NP_001394021 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002292	Orn/put_carbamltrans	Family
IPR006130	Asp/Orn_carbamoylTrfase	Family
IPR006131	Asp_carbamoyltransf_Asp/Orn-bd	Domain
IPR006132	Asp/Orn_carbamoyltranf_P-bd	Domain
IPR036901	Asp/Orn_carbamoylTrfase_sf	Homologous_superfamily

Pfam: PF00185, PF02729

Enzyme classification (BRENDA):

• EC 2.1.3.3 — ornithine carbamoyltransferase (BRENDA: 75 organisms, 81 substrates, 112 inhibitors, 120 Km, 75 kcat entries)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
L-ORNITHINE	0.001–350	67
CARBAMOYL PHOSPHATE	0.0008–5.6	38
ORNITHINE	0.8–1.85	5
CARBAMOYLPHOSPHATE	0.033–0.25	3
DIAMINOBUTANE	43.5	1
L-CITRULLINE	10.4	1
L-LYSINE	25	1
PHOSPHATE	2.3	1

Catalyzed reactions (Rhea), 1 shown:

• carbamoyl phosphate + L-ornithine = L-citrulline + phosphate + H(+) (RHEA:19513)

UniProt features (189 total): sequence variant 121, modified residue 21, helix 15, binding site 10, strand 9, turn 6, mutagenesis site 3, transit peptide 1, chain 1, sequence conflict 1, active site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
1OTH	X-RAY DIFFRACTION	1.85
1C9Y	X-RAY DIFFRACTION	1.9
1EP9	X-RAY DIFFRACTION	2.4
1FVO	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P00480-F1	91.94	0.87

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): 303 (proton acceptor)

Ligand- & substrate-binding residues (10): 268; 303–304; 330; 90–93; 141; 168; 171; 199; 263; 267

Post-translational modifications (21): 70, 70, 80, 88, 88, 133, 144, 144, 221, 221, 231, 231, 238, 238, 243, 274, 289, 292, 292, 307 …

Mutagenesis-validated functional residues (3):

Position	Phenotype
15	loss of cleavage of the transit peptide and loss of localization to mitochondrial matrix; when associated with g-23 and
23	loss of cleavage of the transit peptide and loss of localization to mitochondrial matrix; when associated with g-15 and
26	loss of cleavage of the transit peptide and loss of localization to mitochondrial matrix; when associated with g-15 and

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1268020	Mitochondrial protein import
R-HSA-70635	Urea cycle
R-HSA-9956551	OTC leader sequence variants cause OTC deficiency
R-HSA-9956553	OTC main chain variants cause OTC deficiency

MSigDB gene sets: 251 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_GLUTAMINE_FAMILY_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_RESPONSE_TO_ZINC_ION, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_GLUTAMINE_FAMILY_AMINO_ACID_METABOLIC_PROCESS, LEE_LIVER_CANCER_CIPROFIBRATE_DN, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, MORF_RAD51L3, GOBP_RESPONSE_TO_METAL_ION, GOBP_DIGESTIVE_SYSTEM_DEVELOPMENT, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS

GO Biological Process (17): urea cycle (GO:0000050), liver development (GO:0001889), L-ornithine catabolic process (GO:0006593), midgut development (GO:0007494), response to xenobiotic stimulus (GO:0009410), response to zinc ion (GO:0010043), L-citrulline biosynthetic process (GO:0019240), response to insulin (GO:0032868), obsolete L-arginine biosynthetic process via ornithine (GO:0042450), monoatomic anion homeostasis (GO:0055081), response to biotin (GO:0070781), ammonium homeostasis (GO:0097272), amino acid metabolic process (GO:0006520), L-arginine biosynthetic process (GO:0006526), ornithine metabolic process (GO:0006591), amino acid biosynthetic process (GO:0008652), response to nutrient levels (GO:0031667)

GO Molecular Function (7): ornithine carbamoyltransferase activity (GO:0004585), phospholipid binding (GO:0005543), amino acid binding (GO:0016597), phosphate ion binding (GO:0042301), identical protein binding (GO:0042802), transferase activity (GO:0016740), carboxyl- or carbamoyltransferase activity (GO:0016743)

GO Cellular Component (3): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial matrix (GO:0005759)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
OTC variants cause OTC deficiency	2
Protein localization	1
Metabolism of amino acids and derivatives	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
biosynthetic process	2
ornithine metabolic process	2
urea metabolic process	1
gland development	1
hepaticobiliary system development	1
L-amino acid catabolic process	1
non-proteinogenic amino acid catabolic process	1
digestive tract development	1
response to chemical	1
response to metal ion	1
amino acid biosynthetic process	1
non-proteinogenic amino acid biosynthetic process	1
response to peptide hormone	1
monoatomic ion homeostasis	1
response to vitamin	1
response to nitrogen compound	1
response to oxygen-containing compound	1
inorganic ion homeostasis	1
primary metabolic process	1
arginine metabolic process	1
glutamate family amino acid biosynthetic process	1
non-proteinogenic amino acid metabolic process	1
amino acid metabolic process	1
response to stimulus	1
carboxyl- or carbamoyltransferase activity	1
lipid binding	1
binding	1
anion binding	1
protein binding	1
catalytic activity	1
transferase activity, transferring one-carbon groups	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

2398 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
OTC	ASL	P04424	891
OTC	ASS1	P00966	875
OTC	NAGS	Q8N159	851
OTC	ARG2	P78540	794
OTC	CPS1	P31327	782
OTC	ARG1	P05089	775
OTC	OAT	P04181	667
OTC	SLC25A15	Q9Y619	607
OTC	GLUL	P15104	597
OTC	AZIN2	Q96A70	593
OTC	ODC1	P11926	590
OTC	ARAF	P07557	588
OTC	AGMAT	Q9BSE5	579
OTC	PAOX	Q6QHF9	578
OTC	CLPP	Q16740	576

IntAct

4 interactions, top by confidence:

A	B	Type	Score
OTC	RTL8C	psi-mi:“MI:0914”(association)	0.530
CFTR	OTC	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (111): TUBB1 (Affinity Capture-MS), POLG (Affinity Capture-MS), NIPSNAP3A (Affinity Capture-MS), NDUFAF7 (Affinity Capture-MS), FDXR (Affinity Capture-MS), ATPAF1 (Affinity Capture-MS), GLS (Affinity Capture-MS), NARS2 (Affinity Capture-MS), FAM127A (Affinity Capture-MS), HARS2 (Affinity Capture-MS), CPS1 (Affinity Capture-MS), OTC (Affinity Capture-MS), OTC (Reconstituted Complex), ACAT1 (Proximity Label-MS), ACOT1 (Proximity Label-MS)

ESM2 similar proteins: A2VCW9, A8E657, O17732, O42644, O59711, O82191, O93918, O94609, P00480, P00481, P11154, P11725, P12628, P16243, P17812, P22178, P22515, P23368, P27443, P31326, P32327, P34105, P36444, P37222, P37223, P43279, P51615, P53396, P84010, P93819, Q02046, Q08062, Q0CLK1, Q32PF2, Q54V77, Q55C16, Q6DIY9, Q6FUD0, Q6PAB3, Q7RZV2

Diamond homologs: A0K9X6, A0RR73, A1ATU5, A1AWA3, A1K7J9, A1TLB7, A1U324, A1VEP9, A1VZY2, A1WUZ6, A2SQ85, A3CU82, A3M663, A4G3H2, A4XLM2, A5UMK3, A5WDJ2, A6Q1W6, A6QC22, A7GZL8, A7H345, A7I3W8, A7ZCL8, A8FM43, A9WQ88, B0V6G5, B2UBA4, B2UML6, B3R6D6, B4E9G6, B7GM02, B7HNP5, B8DHF4, B9IXC5, O19072, O27495, O29013, O50039, O58457, O93656

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
PPARGC1A	“up-regulates quantity by expression”	OTC	“transcriptional regulation”
NCOA1	“up-regulates quantity by expression”	OTC	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

1027 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	327
Likely pathogenic	107
Uncertain significance	203
Likely benign	235
Benign	46

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1038367	NM_000531.6(OTC):c.1020_1028del (p.Leu341_Thr343del)	Pathogenic
1066964	NM_000531.6(OTC):c.505C>T (p.Pro169Ser)	Pathogenic
1072591	NM_000531.6(OTC):c.429T>A (p.Tyr143Ter)	Pathogenic
1076888	NC_000023.10:g.(?38210736)(38281703_?)del	Pathogenic
10986	OTC, DEL	Pathogenic
10987	NM_000531.6(OTC):c.422G>A (p.Arg141Gln)	Pathogenic
10988	NM_000531.6(OTC):c.421C>T (p.Arg141Ter)	Pathogenic
10989	NM_000531.6(OTC):c.332T>C (p.Leu111Pro)	Pathogenic
10990	NM_000531.6(OTC):c.646C>G (p.Gln216Glu)	Pathogenic
10991	NM_000531.6(OTC):c.460G>T (p.Glu154Ter)	Pathogenic
10992	NM_000531.6(OTC):c.134T>C (p.Leu45Pro)	Pathogenic
10996	NM_000531.6(OTC):c.717+2T>C	Pathogenic
10998	NM_000531.6(OTC):c.387-2A>T	Pathogenic
10999	NM_000531.6(OTC):c.829C>T (p.Arg277Trp)	Pathogenic
11000	NM_000531.6(OTC):c.674C>T (p.Pro225Leu)	Pathogenic
11001	NM_000531.6(OTC):c.259G>A (p.Glu87Lys)	Pathogenic
11002	NM_000531.6(OTC):c.148G>T (p.Gly50Ter)	Pathogenic
11003	NM_000531.6(OTC):c.484G>A (p.Gly162Arg)	Pathogenic
11007	NM_000531.6(OTC):c.281G>C (p.Arg94Thr)	Pathogenic
11008	NM_000531.6(OTC):c.912G>T (p.Leu304Phe)	Pathogenic
11009	NM_000531.6(OTC):c.1033T>G (p.Tyr345Asp)	Pathogenic
11010	NM_000531.6(OTC):c.386G>A (p.Arg129His)	Pathogenic
11011	NM_000531.6(OTC):c.444G>C (p.Leu148Phe)	Pathogenic
1395169	NM_000531.6(OTC):c.822del (p.Lys276fs)	Pathogenic
1405368	NC_000023.10:g.(?38240585)(38272343_?)del	Pathogenic
1406820	NM_000531.6(OTC):c.579G>T (p.Trp193Cys)	Pathogenic
1428221	NM_000531.6(OTC):c.303del (p.Phe101fs)	Pathogenic
1454810	NM_000531.6(OTC):c.395C>A (p.Ser132Tyr)	Pathogenic
1455073	NC_000023.10:g.(?38229029)(38229150_?)del	Pathogenic
1456662	NM_000531.6(OTC):c.653_663del (p.Ala218fs)	Pathogenic

SpliceAI

1856 predictions. Top by Δscore:

Variant	Effect	Δscore
X:38352772:CGGT:C	donor_loss	1.0000
X:38352774:G:GG	donor_gain	1.0000
X:38367290:GGT:G	acceptor_gain	1.0000
X:38367425:GAGAG:G	donor_gain	1.0000
X:38367427:GAG:G	donor_gain	1.0000
X:38367430:G:C	donor_loss	1.0000
X:38367430:G:GG	donor_gain	1.0000
X:38369794:A:AG	acceptor_gain	1.0000
X:38369795:G:GG	acceptor_gain	1.0000
X:38371266:GCTGT:G	donor_gain	1.0000
X:38401271:ACAGT:A	acceptor_gain	1.0000
X:38401273:A:AG	acceptor_gain	1.0000
X:38401273:AGT:A	acceptor_gain	1.0000
X:38401274:G:GA	acceptor_gain	1.0000
X:38401274:G:GG	acceptor_gain	1.0000
X:38401274:GT:G	acceptor_gain	1.0000
X:38401274:GTG:G	acceptor_gain	1.0000
X:38401274:GTGT:G	acceptor_gain	1.0000
X:38401274:GTGTA:G	acceptor_gain	1.0000
X:38401424:TCCAG:T	donor_loss	1.0000
X:38401425:CCAG:C	donor_loss	1.0000
X:38401425:CCAGG:C	donor_loss	1.0000
X:38401426:CAG:C	donor_loss	1.0000
X:38401426:CAGGT:C	donor_loss	1.0000
X:38401427:AGG:A	donor_loss	1.0000
X:38401427:AGGT:A	donor_loss	1.0000
X:38401428:GG:G	donor_loss	1.0000
X:38401428:GGTT:G	donor_loss	1.0000
X:38401429:GTTG:G	donor_loss	1.0000
X:38401430:T:A	donor_loss	1.0000

AlphaMissense

2317 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:38403674:T:A	N199K	0.999
X:38403674:T:G	N199K	0.999
X:38408946:A:T	D263V	0.999
X:38367401:T:C	L63P	0.998
X:38369835:T:C	F86L	0.998
X:38369837:T:A	F86L	0.998
X:38369837:T:G	F86L	0.998
X:38369847:A:C	S90R	0.998
X:38369849:T:A	S90R	0.998
X:38369849:T:G	S90R	0.998
X:38401390:C:G	H168D	0.998
X:38403654:T:A	W193R	0.998
X:38403654:T:C	W193R	0.998
X:38403696:A:C	S207R	0.998
X:38403698:C:A	S207R	0.998
X:38403698:C:G	S207R	0.998
X:38408945:G:C	D263H	0.998
X:38408947:C:A	D263E	0.998
X:38408947:C:G	D263E	0.998
X:38408951:T:A	W265R	0.998
X:38408951:T:C	W265R	0.998
X:38411898:C:G	H302D	0.998
X:38411903:C:G	C303W	0.998
X:38411984:A:C	R330S	0.998
X:38411984:A:T	R330S	0.998
X:38369860:G:C	R94T	0.997
X:38401401:G:C	Q171H	0.997
X:38401401:G:T	Q171H	0.997
X:38403661:G:A	G195E	0.997
X:38408946:A:C	D263A	0.997

dbSNP variants (sampled 300 via entrez): RS1000025347 (X:38414132 C>T), RS1000074051 (X:38395835 C>G), RS1000089157 (X:38352008 G>A), RS1000226913 (X:38408399 A>C), RS1000232020 (X:38384890 T>C), RS1000284003 (X:38389485 T>C), RS1000328064 (X:38371098 G>A), RS1000335095 (X:38383866 A>G), RS1000350536 (X:38419808 A>C,T), RS1000367867 (X:38371418 T>C), RS1000381932 (X:38420385 A>G), RS1000430619 (X:38380330 T>C), RS1000651270 (X:38361888 C>T), RS1000675132 (X:38398146 C>T), RS1000769239 (X:38374643 G>A)

Disease associations

OMIM: gene MIM:300461 | disease phenotypes: MIM:311250, MIM:244400, MIM:138990, MIM:306400

GenCC curated gene-disease

Disease	Classification	Inheritance
ornithine carbamoyltransferase deficiency	Definitive	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
ornithine carbamoyltransferase deficiency	Definitive	XL

Mondo (3): ornithine carbamoyltransferase deficiency (MONDO:0010703), primary ciliary dyskinesia (MONDO:0016575), granulomatous disease, chronic, X-linked (MONDO:0010600)

Orphanet (3): Ornithine transcarbamylase deficiency (Orphanet:664), Primary ciliary dyskinesia (Orphanet:244), Chronic granulomatous disease (Orphanet:379)

HPO phenotypes

51 total (30 of 51 shown, HPO-id order):

HPO	Term
HP:0000716	Depression
HP:0000737	Irritability
HP:0000739	Anxiety
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001259	Coma
HP:0001263	Global developmental delay
HP:0001297	Stroke
HP:0001298	Encephalopathy
HP:0001328	Specific learning disability
HP:0001399	Hepatic failure
HP:0001419	X-linked recessive inheritance
HP:0001508	Failure to thrive
HP:0001744	Splenomegaly
HP:0001943	Hypoglycemia
HP:0001950	Respiratory alkalosis
HP:0001951	Episodic ammonia intoxication
HP:0001987	Hyperammonemia
HP:0002013	Vomiting
HP:0002027	Abdominal pain
HP:0002033	Poor suck
HP:0002038	Protein avoidance
HP:0002039	Anorexia
HP:0002045	Hypothermia
HP:0002131	Episodic ataxia
HP:0002181	Cerebral edema
HP:0002329	Drowsiness

GWAS associations

0 associations (top):

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D002925	Ciliary Motility Disorders	C08.200; C09.150; C16.131.077.245.500; C16.320.184.500
D007619	Kartagener Syndrome	C08.127.384.500; C08.200.531; C08.695.501; C09.150.531; C14.240.400.280.500; C14.280.400.280.500; C16.131.077.245.500.531; C16.131.240.400.280.500; C16.131.740.501; C16.131.810.250.500; C16.320.184.500.531; C16.320.480
D020163	Ornithine Carbamoyltransferase Deficiency Disease	C10.228.140.163.100.937.750; C16.320.322.828; C16.320.565.100.940.750; C16.320.565.189.937.750; C18.452.132.100.937.500; C18.452.648.100.940.500; C18.452.648.189.937.500
C564210	Granulomatous Disease, Chronic, Autosomal Dominant Type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2222 (SINGLE PROTEIN)

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

ChEMBL bioactivities

3 potent at pChembl≥5 of 4 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.00	Ki	100	nM	CHEMBL1160567
6.89	Ki	130	nM	CHEMBL1160567
6.70	Ki	200	nM	CHEMBL1160567

PubChem BioAssay actives

3 with measured affinity, of 24 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S)-2-amino-5-[(2-phosphonoacetyl)amino]pentanoic acid	151018: Binding affinity against ornithine transcarbamoylase (OTC) produced by Streptococcus faecalis The buffer taken for this study is 50 mM Tris.HCl, 0.5 mM EDTA at pH 7.0.	ki	0.1000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation	3
Valproic Acid	affects response to substance, decreases expression	3
Aflatoxin B1	affects expression, decreases expression, decreases methylation	3
Cyclosporine	decreases expression	2
dicrotophos	decreases expression	1
methyleugenol	decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
sodium arsenite	decreases expression	1
perfluorooctanoic acid	decreases expression	1
lactacystin	decreases metabolic processing, decreases reaction	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
Rosiglitazone	decreases expression	1
Troglitazone	decreases expression	1
Acetaminophen	decreases expression	1
Aspirin	decreases expression	1
Chenodeoxycholic Acid	affects cotreatment, decreases expression	1
Deoxycholic Acid	affects cotreatment, decreases expression	1
Endosulfan	affects cotreatment, decreases expression	1
Estradiol	decreases expression	1
Glycochenodeoxycholic Acid	affects cotreatment, decreases expression	1
Glycocholic Acid	affects cotreatment, decreases expression	1
Glycodeoxycholic Acid	decreases expression, affects cotreatment	1
N-Nitrosopyrrolidine	decreases expression	1
Oxygen	decreases metabolic processing, decreases reaction	1
Paraquat	decreases import, decreases metabolic processing	1
Phenobarbital	affects expression	1
Tartrazine	affects cotreatment, decreases expression	1
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression	1
Triclosan	decreases expression, affects cotreatment	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL750183	Binding	Binding affinity against ornithine transcarbamoylase (OTC) produced by Streptococcus faecalis The buffer taken for this study is 50 mM maleate, 0.5 mM EDTA at pH 6.0.	alpha-Functionalized phosphonylphosphinates: synthesis and evaluation as transcarbamoylase inhibitors. — J Med Chem

Cellosaurus cell lines

59 cell lines: 54 transformed cell line, 2 induced pluripotent stem cell, 2 cancer cell line, 1 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A4XS	SDQLCHi036-A	Induced pluripotent stem cell	Male
CVCL_A5PC	GM25153	Transformed cell line	Female
CVCL_A5PD	GM25154	Transformed cell line	Female
CVCL_D2YZ	GM25475	Transformed cell line	Male
CVCL_HK82	GM23637	Transformed cell line	Female
CVCL_Y706	GM12604	Finite cell line	Female
CVCL_Y707	GM23387	Transformed cell line	Female
CVCL_Y708	GM23388	Transformed cell line	Male
CVCL_Y709	GM23389	Transformed cell line	Female
CVCL_Y710	GM23390	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05345171	PHASE3	ACTIVE_NOT_RECRUITING	Clinical Study of DTX301 AAV-Mediated Gene Transfer for Ornithine Transcarbamylase (OTC) Deficiency
NCT00718627	PHASE2	COMPLETED	Human Heterologous Liver Cells for Infusion in Children With Urea Cycle Disorders
NCT01599286	PHASE2	COMPLETED	Short-Term Outcome of N-Carbamylglutamate in the Treatment of Acute Hyperammonemia
NCT05526066	PHASE2	TERMINATED	Study for Adolescents and Adults With Ornithine Transcarbamylase Deficiency to Evaluate Safety and Tolerability of ARCT-810
NCT06488313	PHASE2	RECRUITING	A Study to Evaluate the Pharmacodynamics and Safety of ARCT-810 in Participants With OTCD
NCT02871778	PHASE2	COMPLETED	Clearing Lungs With ENaC Inhibition in Primary Ciliary Dyskinesia
NCT07318974	PHASE2	ACTIVE_NOT_RECRUITING	Melatonin Therapy for Improving ICSI Outcomes in Women With Diminished Ovarian Reserve
NCT04416126	PHASE1	COMPLETED	Safety, Tolerability and Pharmacokinetics of ARCT-810 in Healthy Adult Subjects
NCT04442347	PHASE1	COMPLETED	Phase 1b Study to Assess Safety, Tolerability, and Pharmacokinetics of ARCT-810 in Stable Adult Subjects With Ornithine Transcarbamylase Deficiency
NCT06247670	PHASE1	ACTIVE_NOT_RECRUITING	Study of CMP-CPS-001 in Healthy Volunteers and Participants With Abnormal Heterozygous OTC Genotype
NCT05737485	PHASE1	COMPLETED	Study Evaluating the Safety and Tolerability of RCT1100 in Healthy and PCD Subjects
NCT06600425	PHASE1	COMPLETED	A Study to Assess the Safety, Tolerability, Ciliary Rescue, and Pharmacodynamics of RCT1100 in Adults With PCD
NCT06633757	PHASE1	COMPLETED	Study of Inhaled RCT1100 in Adults With PCD Caused by Pathogenic Mutations in the DNAI1 Gene to Measure Mucociliary Clearance
NCT02991144	PHASE1/PHASE2	COMPLETED	Safety and Dose-Finding Study of DTX301 (scAAV8OTC) in Adults With Late-Onset Ornithine Transcarbamylase (OTC) Deficiency
NCT03767270	PHASE1/PHASE2	WITHDRAWN	Safety, Tolerability and PK/PD Evaluation of Intravenous Administration of MRT5201 in Patients With OTC Deficiency
NCT05092685	PHASE1/PHASE2	RECRUITING	Halting Ornithine Transcarbamylase Deficiency With Recombinant AAV in ChildrEn
NCT06255782	PHASE1/PHASE2	RECRUITING	An Open-label Study to Investigate ECUR-506 in Male Babies Less Than 9 Months of Age With Neonatal Onset OTC Deficiency
NCT00472732	Not specified	COMPLETED	Neurologic Injuries in Adults With Urea Cycle Disorders
NCT01421888	Not specified	TERMINATED	The NIH UNI Study: Urea Cycle Disorders, Nutrition and Immunity
NCT01569568	Not specified	COMPLETED	Investigation of Brain Nitrogen in Partial Ornithine Transcarbamylase Deficiency (OTCD) Using 1 H MRS, DTI, and fMRI
NCT03636438	Not specified	ACTIVE_NOT_RECRUITING	Long Term Follow Up to Evaluate DTX301 in Adults With Late-Onset OTC Deficiency
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT04248062	Not specified	COMPLETED	Patient and Observer Reported Outcome Measurements in Inborn Errors of Metabolism
NCT04269122	Not specified	COMPLETED	A Study to Assess Plasma Ammonia Time-Normalized Area Under the Curve and Rate of Ureagenesis in Healthy Adult Subjects
NCT04612764	Not specified	ACTIVE_NOT_RECRUITING	Liver Disease in Urea Cycle Disorders
NCT04717453	Not specified	TERMINATED	Study to Characterize Rate of Ureagenesis in Patients With Ornithine Transcarbamylase (OTC) Deficiency
NCT04908319	Not specified	RECRUITING	Hepatic Histopathology in Urea Cycle Disorders
NCT04909346	Not specified	TERMINATED	Adeno-Associated Virus (AAV) Antibody Study in Subjects OTC Deficiency, GSDIa, and Wilson Disease
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan
NCT06805695	Not specified	RECRUITING	Long-term Follow-up (LTFU) Study of Participants in Any iECURE Protocol Using an Investigational Product (IP)
NCT04901715	EARLY_PHASE1	COMPLETED	Functional Studies of Novel Genes Mutated in Primary Ciliary Dyskinesia II: Genotype to Phenotype
NCT00005650	Not specified	COMPLETED	Genetic Study of Patients With Primary Ciliary Dyskinesia
NCT00323167	Not specified	COMPLETED	Rare Genetic Disorders of the Breathing Airways
NCT00368446	Not specified	COMPLETED	Genetic Disorders of Mucociliary Clearance in Nontuberculous Mycobacterial Lung Disease
NCT00450918	Not specified	COMPLETED	Evaluating Progression of and Diagnostic Tools for Primary Ciliary Dyskinesia in Children and Adolescents
NCT00608556	Not specified	COMPLETED	Dyskinesia, Heterotaxy and Congenital Heart Disease
NCT00686309	Not specified	UNKNOWN	Comparison of On-line and Off-line Measurements of Exhaled Nitric Oxide (NO)
NCT00722878	Not specified	COMPLETED	Long-term Lung Function and Disease Progression in Children With Early Onset Primary Ciliary Dyskinesia Lung Disease
NCT00739817	Not specified	UNKNOWN	Screening for Primary Ciliary Dyskinesia Using Nasal Nitric Oxide