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): 1,041 total — 324 pathogenic, 116 likely-pathogenic (top 3% of genes corpus-wide)
• GTEx eGene: eQTL in 11 tissues, sQTL in 1 (q < 0.05)
• Phenotypes (HPO): 51
• 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: 23 — 14 protein_coding, 8 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000039007

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 5: 1

ENST00000039007, ENST00000488812, ENST00000643344, ENST00000713758, ENST00000713759, ENST00000713760, ENST00000909233, ENST00000909234, ENST00000909235, ENST00000909236, ENST00000909237, ENST00000909238, ENST00000909239, ENST00000909240, ENST00000909241, ENST00000996698, ENST00000996699, ENST00000996700, ENST00000996701, ENST00000996704, ENST00000996706, ENST00001109701, ENST00001133588

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.

Highest expression (Bgee): jejunal mucosa, lobe of liver, liver, duodenum, mucosa of transverse colon.

Genetic regulation across tissues (GTEx eQTL / sQTL)

OTC is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 11 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

12 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Nerve Tibial	eqtl	4.5e-11	+0.29	X:38353210:C:A
Artery Tibial	eqtl	7.1e-06	+0.17	X:38353210:C:A
Heart Atrial Appendage	eqtl	1.2e-05	+0.29	X:38353210:C:A
Thyroid	eqtl	8.9e-05	+0.17	X:38341888:A:G
Adipose Subcutaneous	eqtl	3.6e-04	+0.14	X:38342512:A:G
Esophagus Mucosa	eqtl	9.5e-04	+0.19	X:38353210:C:A
Lung	eqtl	6.8e-03	+0.14	X:38358095:G:A
Testis	sqtl	1.3e-02	+0.28	X:38356667:A:G
Brain Cerebellum	eqtl	1.9e-02	+1.18	X:38661792:C:A
Testis	eqtl	2.7e-02	+0.19	X:38356224:G:GAC
Skin Not Sun Exposed Suprapubic	eqtl	2.8e-02	+0.14	X:38341888:A:G
Brain Anterior cingulate cortex BA24	eqtl	4.1e-02	+1.17	X:38985374:G:A

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

showing 100 of 288 tissues 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
left ventricle myocardium	UBERON:0006566	52.52	gold quality
coronary artery	UBERON:0001621	52.40	gold quality
left coronary artery	UBERON:0001626	52.31	gold quality
colonic epithelium	UBERON:0000397	51.71	gold quality
body of uterus	UBERON:0009853	51.50	gold quality
hair follicle	UBERON:0002073	51.16	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	50.94	gold quality
frontal pole	UBERON:0002795	50.41	gold quality
quadriceps femoris	UBERON:0001377	50.40	gold quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality
paraflocculus	UBERON:0005351	50.18	gold quality
Brodmann (1909) area 10	UBERON:0013541	50.18	gold quality
spinal cord	UBERON:0002240	50.03	gold quality
upper lobe of left lung	UBERON:0008952	49.83	gold quality
vastus lateralis	UBERON:0001379	49.80	gold quality
ectocervix	UBERON:0012249	49.77	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.75	gold quality
oocyte	CL:0000023	49.57	gold quality
fallopian tube	UBERON:0003889	49.52	gold quality
thymus	UBERON:0002370	49.37	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
myocardium	UBERON:0002349	49.27	gold quality
lung	UBERON:0002048	49.23	gold quality
upper lobe of lung	UBERON:0008948	49.21	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
tibialis anterior	UBERON:0001385	49.09	silver quality
olfactory bulb	UBERON:0002264	48.92	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
fundus of stomach	UBERON:0001160	48.70	gold quality
omental fat pad	UBERON:0010414	48.62	gold quality
peritoneum	UBERON:0002358	48.59	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality
oviduct epithelium	UBERON:0004804	48.41	gold quality
colonic mucosa	UBERON:0000317	48.27	gold quality
orbitofrontal cortex	UBERON:0004167	48.20	gold quality
adipose tissue of abdominal region	UBERON:0007808	48.17	gold quality
lymph node	UBERON:0000029	48.09	gold quality
upper arm skin	UBERON:0004263	48.06	gold quality
cervix epithelium	UBERON:0004801	48.04	gold quality
endocervix	UBERON:0000458	47.98	gold quality
tongue squamous epithelium	UBERON:0006919	47.92	gold quality
mucosa of urinary bladder	UBERON:0001259	47.80	gold quality
uterine cervix	UBERON:0000002	47.78	gold quality
metanephric glomerulus	UBERON:0004736	47.74	gold quality
nasal cavity epithelium	UBERON:0005384	47.70	gold quality
renal glomerulus	UBERON:0000074	47.60	gold quality
kidney epithelium	UBERON:0004819	47.48	gold quality
deltoid	UBERON:0001476	47.47	gold quality
descending thoracic aorta	UBERON:0002345	47.36	gold quality
substantia nigra	UBERON:0002038	47.21	gold quality
myometrium	UBERON:0001296	47.15	gold quality
periodontal ligament	UBERON:0008266	47.14	gold quality
gluteal muscle	UBERON:0002000	47.03	gold quality
triceps brachii	UBERON:0001509	47.01	gold quality
cardiac atrium	UBERON:0002081	46.99	gold quality
nephron tubule	UBERON:0001231	46.88	gold quality
right atrium auricular region	UBERON:0006631	46.70	gold quality
midbrain	UBERON:0001891	46.42	gold quality
ascending aorta	UBERON:0001496	46.40	gold quality
thoracic aorta	UBERON:0001515	46.35	gold quality
muscle tissue	UBERON:0002385	46.19	gold quality
prefrontal cortex	UBERON:0000451	46.13	gold quality
layer of synovial tissue	UBERON:0007616	45.76	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	45.35	gold quality
inferior olivary complex	UBERON:0002127	45.14	gold quality
hypothalamus	UBERON:0001898	45.03	gold quality
lateral globus pallidus	UBERON:0002476	44.51	gold quality
metanephros	UBERON:0000081	44.33	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

HPA expression

RNA tissue specificity: Group enriched

57 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Liver	tissue	353.1	high
Duodenum	tissue	105.7	high
Small intestine	tissue	82.3	high
Corpus callosum	tissue	10.5
Colon	tissue	4.6	low
Putamen	tissue	4.5
Substantia nigra	tissue	4.2
Ventral forebrain	tissue	3.9
Hypothalamus	tissue	3.8
Midbrain	tissue	3.7
Periaqueductal gray	tissue	3.7
Septum	tissue	3.6
Spinal cord	tissue	3.4
Medulla oblongata	tissue	3.3
Hippocampal formation	tissue	3.3
Pons	tissue	3.2
Thalamus	tissue	2.9
Basal ganglia	tissue	2.5	not detected
Amygdala	tissue	2.5
Rectum	tissue	2.4	medium
Superior colliculi	tissue	2.3
Stomach 1	tissue	1.8	not detected
Cerebral cortex	tissue	1.8	not detected
Retrosplenial cortex	tissue	1.8
Insular cortex	tissue	1.8
Pancreas	tissue	1.6	not detected
Motor cortex	tissue	1.5
Entorhinal cortex	tissue	1.4
Retrosplenial and cingulate cortex	tissue	1.4
Somatosensory cortex	tissue	1.4
Occipital cortex	tissue	1.4
Temporal cortex	tissue	1.3
Prefrontal cortex	tissue	1.2
Olfactory bulb	tissue	1.2
Adipose tissue	tissue	1.1	not detected
Lung	tissue	0.9	not detected
Endometrium 1	tissue	0.7	not detected
Cerebellum	tissue	0.6	not detected
Smooth muscle	tissue	0.5	not detected
Fallopian tube	tissue	0.5	not detected
Cervix	tissue	0.4	not detected
Testis	tissue	0.4	not detected
Gallbladder	tissue	0.4	not detected
Locus coeruleus	tissue	0.4
Appendix	tissue	0.4	medium
Vagina	tissue	0.3	not detected
Esophagus	tissue	0.3	not detected
Thyroid gland	tissue	0.3	not detected
Nucleus accumbens	tissue	0.2
Postcentral gyrus	tissue	0.2
Lymph node	tissue	0.1	not detected
Heart muscle	tissue	0.1	not detected
Retina	tissue	0.1
Seminal vesicle	tissue	0.1	not detected
Salivary gland	tissue	0.1	not detected
Kidney	tissue	0.1	not detected
Hippocampus	tissue	0.1	not detected

Brain sub-regions (HPA Brain Atlas): detected in 184; highest nTPM — White matter (10.5), Ventral spinal cord (3.4), Dorsal hippocampus (3.3), Dorsal spinal cord (3.0), Ventral hippocampus (2.0).

Regulation

Is transcription factor: no

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

miRNA regulators (miRDB)

Targeting OTC by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 35 miRNAs:

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

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000039007 — one region, missense o/e 0.75. 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)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:97448) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 70 distinct phenotype terms.

Mouse phenotype (MP)	Records
sparse hair	8
increased circulating ammonia level	7
decreased body size	6
decreased ornithine carbamoyltransferase activity	6
abnormal brain morphology	5
oroticaciduria	5
wrinkled skin	4
abnormal circulating amino acid level	3
abnormal amino acid level	3
abnormal enzyme/coenzyme activity	3
focal hair loss	2
abnormal liver morphology	2
hyperactivity	2
abnormal metabolism	2
orotic acid urinary bladder stones	2
decreased liver enzyme/coenzyme activity	2
increased circulating glutamine level	2
alopecia	1
delayed hair appearance	1
abnormal head movements	1
enlarged liver	1
enlarged thymus	1
tremors	1
decreased brain size	1
abnormal testis morphology	1

+45 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Aspergillus terreus	P0C2P2	100.0%	Diamond
Aspergillus terreus NIH2624	P0C2P3	100.0%	Diamond
Streptococcus ratti	B7S4N1	99.1%	Diamond
Streptococcus mutans UA159	Q8DW19	99.1%	Diamond
Ovis aries	P84010	98.3%	Diamond
Bos taurus	Q9N1U7	98.3%	Diamond
Sus scrofa	O19072	95.7%	Diamond
Aspergillus nidulans FGSC A4	P11803	86.0%	Diamond
Campylobacter curvus 525.92	A7GZL8	83.9%	Diamond
Campylobacter concisus 13826	A7ZCL8	83.9%	Diamond
Aspergillus niger	P11066	82.1%	Diamond
Aquarana catesbeiana	P31326	81.7%	Diamond
Sulfurovum sp. NBC37-1	A6QC22	79.6%	Diamond
Lactococcus lactis subsp. lactis Il1403	Q9CEY4	79.6%	Diamond
Coccidioides immitis RS	P0CL21	79.0%	Diamond
Gallus gallus	Q9YHY9	78.9%	Diamond
Campylobacter fetus subsp. fetus 82-40	A0RR73	72.0%	Diamond
Campylobacter hominis ATCC BAA-381	A7I3W8	71.4%	Diamond
Carboxydothermus hydrogenoformans Z-2901	Q3A9W4	63.3%	Diamond
Schizosaccharomyces pombe 972h-	P31317	57.2%	Diamond
Pachysolen tannophilus	P14995	57.1%	Diamond
Saccharomyces cerevisiae S288C	P05150	56.4%	Diamond
Trametes hirsuta	P78605	46.3%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
TSPAN7	protein-coding	7102
RPGR	protein-coding	6103
MIR548AJ2	ncRNA	100616252
SRPX	protein-coding	8406
SYTL5	protein-coding	94122

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)

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

UniProt features (192 total): sequence variant 121, modified residue 21, helix 18, 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 by resolution:

PDB	Title	Method	Resolution (Å)
1OTH	CRYSTAL STRUCTURE OF HUMAN ORNITHINE TRANSCARBAMOYLASE COMPLEXED WITH …	X-RAY DIFFRACTION	1.85
1C9Y	HUMAN ORNITHINE TRANSCARBAMYLASE: CRYSTALLOGRAPHIC INSIGHTS INTO SUBSTRATE RECOGNITION …	X-RAY DIFFRACTION	1.9
1EP9	HUMAN ORNITHINE TRANSCARBAMYLASE: CRYSTALLOGRAPHIC INSIGHTS INTO SUBSTRATE RECOGNITION …	X-RAY DIFFRACTION	2.4
1FVO	CRYSTAL STRUCTURE OF HUMAN ORNITHINE TRANSCARBAMYLASE COMPLEXED WITH CARBAMOYL PHOSPHATE	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Metabolic proteins, Predicted intracellular proteins, Plasma proteins, Disease related genes, Potential drug targets, Human disease related genes, Congenital disorders of metabolism, Congenital disorders of amino acid metabolism

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): mitochondria

Antibody reliability (HPA): IH enhanced · IF supported

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)

Position	Role
303	proton acceptor

Ligand- & substrate-binding residues (10)

Position	Role
268	L-ornithine
303–304	carbamoyl phosphate
330	carbamoyl phosphate
90–93	carbamoyl phosphate
141	carbamoyl phosphate
168	carbamoyl phosphate
171	carbamoyl phosphate
199	L-ornithine
263	L-ornithine
267	L-ornithine

Post-translational modifications (21)

Type	Positions
N6-acetyllysine	70, 88, 144, 221, 231, 238, 243, 292, 307
N6-succinyllysine	70, 80, 88, 144, 221, 231, 238, 274, 289, 292, 307
Phosphoserine	133

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

Function

Pathways and Gene Ontology

Reactome pathways

4 curated (TAS) of 8; 2 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

8 pathways:

ID	Pathway	Evidence
R-HSA-9956551	OTC leader sequence variants cause OTC deficiency ⚕	curated
R-HSA-9956553	OTC main chain variants cause OTC deficiency ⚕	curated
R-HSA-9988426	Negative transcriptional regulation of urea cycle enzymes	curated
R-HSA-70635	Urea cycle	curated
R-HSA-1430728	Metabolism	—
R-HSA-71291	Metabolism of amino acids and derivatives	—
R-HSA-1268020	Mitochondrial protein import	electronic
R-HSA-9609507	Protein localization	—

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 (16): 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), 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

5 top-level categories:

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

GO top-level categories

37 GO namespaces:

Category	Terms
biosynthetic process	2
ornithine metabolic process	2
urea metabolic process	1
gland development	1
hepaticobiliary system development	1
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

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 6 of 27 annotations. The rest are phylogenetic / computational / electronic (IEA).

6 experimentally-supported GO terms:

GO term	NS	Evidence
L-citrulline biosynthetic process	BP	direct assay
L-ornithine catabolic process	BP	direct assay
ammonium homeostasis	BP	mutant phenotype
urea cycle	BP	direct assay
mitochondrion	CC	direct assay
ornithine carbamoyltransferase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,653 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
OTC	ASS1	P00966	864
OTC	ASL	P04424	852
OTC	NAGS	Q8N159	846
OTC	CPS1	P31327	768
OTC	ARG2	P78540	760
OTC	ARG1	P05089	745
OTC	OAT	P04181	668
OTC	SLC25A15	Q9Y619	609
OTC	PAOX	Q6QHF9	582
OTC	AZIN2	Q96A70	576
OTC	ALDH18A1	P54886	572
OTC	ARAF	P07557	571
OTC	ODC1	P11926	554
OTC	SLC7A7	Q9UM01	546
OTC	AGMAT	Q9BSE5	536

IntAct

Human interaction partners of OTC in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

2 partners by confidence:

Partner	Interaction type	MIscore	Records
RTL8C	association	0.530	2
CFTR	physical association	0.370	1

BioGRID (111 interactions; top human partners by supporting records): ATPAF1 (Affinity Capture-MS; 2 records), FAM127A (Affinity Capture-MS; 2 records), FDXR (Affinity Capture-MS; 2 records), GLS (Affinity Capture-MS; 2 records), NARS2 (Affinity Capture-MS; 2 records), POLG (Affinity Capture-MS; 2 records), TUBB1 (Affinity Capture-MS; 2 records), ACAT1 (Proximity Label-MS), ACOT1 (Proximity Label-MS), ACOT2 (Proximity Label-MS), AFG3L2 (Proximity Label-MS), ATP5B (Proximity Label-MS), ATP5F1 (Proximity Label-MS), ATP5J (Proximity Label-MS), CFTR (PCA)

SIGNOR signaling

2 signaling 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

Genetic variants

Variant evidence for OTC: 1,041 ClinVar records (440 pathogenic / likely pathogenic); 45 ClinGen expert-panel interpretations. Per-variant detail is on Sugi Variant.

ClinVar

1,041 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	324
Likely pathogenic	116
Uncertain significance	207
Likely benign	237
Benign	43

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 440 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
97274	NM_000531.6(OTC):c.622G>A (p.Ala208Thr)	Pathogenic	criteria provided, multiple submitters, no conflicts	16
449382	NM_000531.6(OTC):c.540+265G>A	Pathogenic	criteria provided, multiple submitters, no conflicts	13
10999	NM_000531.6(OTC):c.829C>T (p.Arg277Trp)	Pathogenic	criteria provided, multiple submitters, no conflicts	12
10987	NM_000531.6(OTC):c.422G>A (p.Arg141Gln)	Pathogenic	criteria provided, multiple submitters, no conflicts	11
11000	NM_000531.6(OTC):c.674C>T (p.Pro225Leu)	Pathogenic	criteria provided, multiple submitters, no conflicts	10
11010	NM_000531.6(OTC):c.386G>A (p.Arg129His)	Pathogenic	criteria provided, multiple submitters, no conflicts	10
97152	NM_000531.6(OTC):c.275G>A (p.Arg92Gln)	Pathogenic	criteria provided, multiple submitters, no conflicts	9
97371	NM_000531.6(OTC):c.958C>T (p.Arg320Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	9
97216	NM_000531.6(OTC):c.482A>G (p.Asn161Ser)	Pathogenic	criteria provided, multiple submitters, no conflicts	8
97237	NM_000531.6(OTC):c.533C>T (p.Thr178Met)	Pathogenic	criteria provided, multiple submitters, no conflicts	8
97275	NM_000531.6(OTC):c.626C>T (p.Ala209Val)	Pathogenic	criteria provided, multiple submitters, no conflicts	8
97292	NM_000531.6(OTC):c.67C>T (p.Arg23Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	7
487338	NM_000531.6(OTC):c.-106C>A	Pathogenic	criteria provided, multiple submitters, no conflicts	7
97255	NM_000531.6(OTC):c.583G>A (p.Gly195Arg)	Pathogenic	criteria provided, multiple submitters, no conflicts	6
97339	NM_000531.6(OTC):c.830G>A (p.Arg277Gln)	Pathogenic	criteria provided, multiple submitters, no conflicts	5

Per-variant reference — Sugi Variant

Explore OTC’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

ClinGen expert-panel interpretations (45)

Expert ACMG interpretations from Urea Cycle Disorders VCEP for ornithine carbamoyltransferase deficiency — a higher-authority tier than individual ClinVar submissions.

Assertion	Variants
Pathogenic	9
Likely Pathogenic	15
Uncertain Significance	8
Likely Benign	2
Benign	11

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 25 predictions of 748):

Position(s)	Effect	Δscore	Sites
X:38352774–38352775	donor_loss	1.0000	5
X:38367430	donor_loss	1.0000	2
X:38401429–38401430	donor_loss	1.0000	5
X:38367290	acceptor_loss	0.9900	2
X:38367431	donor_loss	0.9900
X:38369813	acceptor_gain	0.9900
X:38371270	donor_gain	0.9900
X:38401262	acceptor_gain	0.9900
X:38401272	acceptor_gain	0.9900
X:38401273–38401274	acceptor_loss	0.9900	6

AlphaMissense

993 missense substitutions predicted likely pathogenic (of 2,317 scored), across 237 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M268	9	0.906	0.982
D263	8	0.996	0.999
H302	8	0.989	0.998
D175	8	0.983	0.993
H168	8	0.982	0.998
F86	8	0.981	0.998
S90	8	0.979	0.998
D196	8	0.978	0.992
D126	8	0.974	0.988
N199	8	0.972	0.999
N329	8	0.960	0.991
S267	8	0.956	0.997
F281	8	0.953	0.990
D115	8	0.949	0.988
F300	8	0.938	0.995
F316	8	0.927	0.987
D62	8	0.870	0.928
H117	8	0.799	0.967
F101	8	0.792	0.965
W265	7	0.990	0.998

HPA cancer prognostics

RNA cancer specificity: Cancer enriched (Liver Hepatocellular Carcinoma)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Rectum Adenocarcinoma (validation)	unfavorable	0.000834

Disease associations

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

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
ornithine carbamoyltransferase deficiency	Definitive	X-linked	6

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
ornithine carbamoyltransferase deficiency	Definitive	XL

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (9 panels, 9 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

9 panels:

Panel	Rating
DDG2P	green
Hyperammonaemia	green
Hypotonic infant	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Likely inborn error of metabolism	green
Paediatric disorders	green
Undiagnosed metabolic disorders	green
Unexplained death in infancy and sudden unexplained death in childhood	green

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 phenotypes (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
HP:0002572	Episodic vomiting
HP:0002908	Conjugated hyperbilirubinemia
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003217	Hyperglutaminemia
HP:0003218	Oroticaciduria
HP:0003355	Aminoaciduria
HP:0003572	Decreased circulating citrulline concentration
HP:0003581	Adult onset
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0003623	Neonatal onset
HP:0003645	Prolonged partial thromboplastin time
HP:0005961	Hypoargininemia
HP:0007018	Attention deficit hyperactivity disorder
HP:0008151	Prolonged prothrombin time
HP:0011463	Childhood onset
HP:0031258	Delirium
HP:0031956	Elevated circulating aspartate aminotransferase concentration
HP:0031964	Elevated circulating alanine aminotransferase concentration
HP:0033139	Elevated circulating uracil concentration
HP:6000334	Reduced hepatic ornithine transcarbamylase activity

MeSH disease descriptors

4 disease descriptors:

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 (CPIC guideline: no)

Binding affinities (BindingDB)

7 measured of 7 human assays (8 total across all organisms); most potent 7 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
2-Amino-5-(2-phosphono-acetylamino)-pentanoic acid	KI	100 nM
Medronic acid	IC50	49000 nM
diphosphate	IC50	181000 nM
(Aminomethyl-hydroxy-phosphinoylmethyl)-phosphonic acid	KI	265000 nM
(2S)-2-[(tert-butoxycarbonyl)amino]-5-[({[(hydroxyphosphinato)methyl]phosphinato}methyl)ammonio]pentanoate	KI	1e+06 nM
2-Amino-5-[(hydroxy-phosphonomethyl-phosphinoylmethyl)-amino]-pentanoic acid	KI	1.9e+06 nM
(2S)-2-ammonio-4-[({[(hydroxyphosphinato)methyl]phosphinato}methyl)ammonio]butanoate	KI	2.3e+06 nM

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	decreases expression, affects response to substance	3
Aflatoxin B1	decreases expression, decreases methylation, affects expression	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	affects cotreatment, decreases expression	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	decreases expression, affects cotreatment	1
Triclosan	affects cotreatment, decreases expression	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)

Via MONDO — disease-level, not drug-specific.

showing 60 of 103 trials:

NCT	Phase	Status	Title
NCT05345171	Phase 3	ACTIVE_NOT_RECRUITING	Clinical Study of DTX301 AAV-Mediated Gene Transfer for Ornithine Transcarbamylase (OTC) Deficiency
NCT06255782	Phase 3	RECRUITING	An Open-label Study to Investigate ECUR-506 in Male Babies Less Than 9 Months of Age With Neonatal Onset OTC Deficiency
NCT00718627	Phase 2	COMPLETED	Human Heterologous Liver Cells for Infusion in Children With Urea Cycle Disorders
NCT01599286	Phase 2	COMPLETED	Short-Term Outcome of N-Carbamylglutamate in the Treatment of Acute Hyperammonemia
NCT05526066	Phase 2	TERMINATED	Study for Adolescents and Adults With Ornithine Transcarbamylase Deficiency to Evaluate Safety and Tolerability of ARCT-810
NCT06488313	Phase 2	RECRUITING	A Study to Evaluate the Pharmacodynamics and Safety of ARCT-810 in Participants With OTCD
NCT02871778	Phase 2	COMPLETED	Clearing Lungs With ENaC Inhibition in Primary Ciliary Dyskinesia
NCT07318974	Phase 2	ACTIVE_NOT_RECRUITING	Melatonin Therapy for Improving ICSI Outcomes in Women With Diminished Ovarian Reserve
NCT04416126	Phase 1	COMPLETED	Safety, Tolerability and Pharmacokinetics of ARCT-810 in Healthy Adult Subjects
NCT04442347	Phase 1	COMPLETED	Phase 1b Study to Assess Safety, Tolerability, and Pharmacokinetics of ARCT-810 in Stable Adult Subjects With Ornithine Transcarbamylase Deficiency
NCT06247670	Phase 1	ACTIVE_NOT_RECRUITING	Study of CMP-CPS-001 in Healthy Volunteers and Participants With Abnormal Heterozygous OTC Genotype
NCT05737485	Phase 1	COMPLETED	Study Evaluating the Safety and Tolerability of RCT1100 in Healthy and PCD Subjects
NCT06600425	Phase 1	COMPLETED	A Study to Assess the Safety, Tolerability, Ciliary Rescue, and Pharmacodynamics of RCT1100 in Adults With PCD
NCT06633757	Phase 1	COMPLETED	Study of Inhaled RCT1100 in Adults With PCD Caused by Pathogenic Mutations in the DNAI1 Gene to Measure Mucociliary Clearance
NCT02991144	Phase 1/2	COMPLETED	Safety and Dose-Finding Study of DTX301 (scAAV8OTC) in Adults With Late-Onset Ornithine Transcarbamylase (OTC) Deficiency
NCT03767270	Phase 1/2	WITHDRAWN	Safety, Tolerability and PK/PD Evaluation of Intravenous Administration of MRT5201 in Patients With OTC Deficiency
NCT05092685	Phase 1/2	RECRUITING	Halting Ornithine Transcarbamylase Deficiency With Recombinant AAV in ChildrEn
NCT07773246	Phase 1/2	NOT_YET_RECRUITING	Phase 1/2 Study of KRRO-121 in Healthy Volunteers and Patients With UCD
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	ACTIVE_NOT_RECRUITING	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 Phase 1	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
NCT00783887	Not specified	COMPLETED	Diagnosis of Primary Ciliary Dyskinesia
NCT00807482	Not specified	RECRUITING	Pathogenesis of Primary Ciliary Dyskinesia (PCD) Lung Disease
NCT01070914	Not specified	UNKNOWN	Early Detection and Characterization of Primary Ciliary Dyskinesia
NCT01155115	Not specified	COMPLETED	Inflammatory and Microbiologic Markers in Sputum: Comparing Cystic Fibrosis With Primary Ciliary Dyskinesia
NCT01246258	Not specified	COMPLETED	Otolith Function in Patients With Primary Ciliary Dyskinesia
NCT01929356	Not specified	UNKNOWN	Chest Physiotherapy and Lung Function in Primary Ciliary Dyskinesia
NCT02389049	Not specified	COMPLETED	Genetics of Primary Ciliary Dyskinesia
NCT02419365	Not specified	RECRUITING	International Primary Ciliary Dyskinesia (PCD) Registry
NCT02622061	Not specified	COMPLETED	NIOX VERO Nasal Application in Primary Ciliary Dyskinesia
NCT02699177	Not specified	UNKNOWN	In Vivo Measurements of Nasal Ciliary Beat Frequency by Using Interferometry
NCT02704455	Not specified	NOT_YET_RECRUITING	Registry Study on Primary Ciliary Dyskinesia in Chinese Children
NCT03271840	Not specified	COMPLETED	Registry for Primary Ciliary Dyskinesia
NCT03279965	Not specified	UNKNOWN	MRI in Cystic Fibrosis and Primary Ciliary Dyskinesia
NCT03320382	Not specified	UNKNOWN	Multiple Breath Washout, a Clinimetric Dataset
NCT03370029	Not specified	COMPLETED	Respiratory Muscle Strength, Exercise Capacity and Physical Activity Levels in Children Primary Ciliary Dyskinesia
NCT03494894	Not specified	COMPLETED	Bacteriological Link Between Upper and Lower Airways in Cystic Fibrosis and Primary Ciliary Dyskinesia
NCT03517865	Not specified	ACTIVE_NOT_RECRUITING	International Primary Ciliary Dyskinesia Cohort
NCT03606200	Not specified	RECRUITING	Swiss Primary Ciliary Dyskinesia Registry
NCT03704207	Not specified	RECRUITING	Utility of PCD Diagnostics to Improve Clinical Care

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for OTC across ~30M SureChEMBL compounds — explore on Sugi Predict.