UROC1

Summary

UROC1 (urocanate hydratase 1, HGNC:26444) is a protein-coding gene on chromosome 3q21.3, encoding Urocanate hydratase (Q96N76).

This gene encodes an enzyme involved in the second step of histidine catabolism, metabolizing urocanic acid to formiminoglutamic acid. Deficiency of this enzyme results in urocanic aciduria, and is an apparent cause of mental retardation. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 131669 — RefSeq curated summary.

At a glance

• Gene–disease (curated): urocanic aciduria (Moderate, GenCC)
• GWAS associations: 9
• Clinical variants (ClinVar): 212 total — 3 pathogenic
• Phenotypes (HPO): 18
• MANE Select transcript: NM_144639

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26444
Approved symbol	UROC1
Name	urocanate hydratase 1
Location	3q21.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ31300, HMFN0320
Ensembl gene	ENSG00000159650
Ensembl biotype	protein_coding
OMIM	613012
Entrez	131669

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 8 protein_coding

ENST00000290868, ENST00000383579, ENST00000875183, ENST00000875184, ENST00000875185, ENST00000875186, ENST00000875187, ENST00000966761

RefSeq mRNA: 2 — MANE Select: NM_144639 NM_001165974, NM_144639

CCDS: CCDS3038, CCDS54636

Canonical transcript exons

ENST00000290868 — 20 exons

Exon	Start	End
ENSE00001046918	126489276	126489375
ENSE00001046921	126488198	126488279
ENSE00001079392	126501218	126501280
ENSE00001079393	126483369	126483468
ENSE00001079396	126505945	126506011
ENSE00001079397	126508416	126508475
ENSE00001079398	126509585	126509678
ENSE00001079400	126500695	126500874
ENSE00001079402	126507742	126507803
ENSE00001079403	126499337	126499409
ENSE00001079404	126496038	126496108
ENSE00001079405	126505701	126505844
ENSE00001079406	126507967	126508095
ENSE00001079407	126510664	126510794
ENSE00001079408	126498051	126498172
ENSE00001079409	126492418	126492516
ENSE00001079410	126503995	126504083
ENSE00001079411	126500057	126500154
ENSE00001228599	126481166	126482485
ENSE00002026885	126517594	126517773

Expression profiles

Bgee: expression breadth broad, 41 present calls, max score 94.82.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2868 / max 175.5374, expressed in 15 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
44350	0.1691	10
44351	0.1177	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	94.82	gold quality
liver	UBERON:0002107	84.88	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.77	gold quality
right uterine tube	UBERON:0001302	64.76	gold quality
parotid gland	UBERON:0001831	61.87	gold quality
cerebellar vermis	UBERON:0004720	54.64	gold quality
buccal mucosa cell	CL:0002336	52.73	gold quality
oocyte	CL:0000023	50.58	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	49.05	gold quality
cortical plate	UBERON:0005343	46.69	gold quality
prefrontal cortex	UBERON:0000451	46.39	silver quality
thymus	UBERON:0002370	45.79	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	45.05	silver quality
nasal cavity mucosa	UBERON:0001826	44.69	gold quality
quadriceps femoris	UBERON:0001377	44.39	gold quality
skin of hip	UBERON:0001554	44.28	silver quality
muscle of leg	UBERON:0001383	44.19	gold quality
skeletal muscle tissue	UBERON:0001134	43.95	gold quality
gastrocnemius	UBERON:0001388	43.83	gold quality
frontal cortex	UBERON:0001870	43.77	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
deltoid	UBERON:0001476	43.16	gold quality
amniotic fluid	UBERON:0000173	42.82	gold quality
neocortex	UBERON:0001950	42.79	silver quality
Brodmann (1909) area 9	UBERON:0013540	42.64	silver quality
secondary oocyte	CL:0000655	42.57	gold quality
fallopian tube	UBERON:0003889	42.53	gold quality
bone marrow cell	CL:0002092	42.32	gold quality
right frontal lobe	UBERON:0002810	42.29	silver quality
ganglionic eminence	UBERON:0004023	42.21	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	2.78

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

35 targeting UROC1, 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-4455	100.00	65.48	1587
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-1324	99.46	66.57	1302
HSA-MIR-6828-5P	99.31	69.21	1433
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-4667-3P	99.26	65.45	1608
HSA-MIR-3191-5P	99.24	66.52	1722
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-6884-5P	99.10	64.50	1987
HSA-MIR-485-5P	99.10	64.78	1889
HSA-MIR-2355-5P	98.83	65.51	1589
HSA-MIR-3135B	98.61	65.33	1470
HSA-MIR-3944-5P	98.50	67.55	997
HSA-MIR-3138	98.41	67.53	744
HSA-MIR-4664-5P	98.17	65.07	1020
HSA-MIR-4457	98.09	67.12	1274
HSA-MIR-3652	97.71	65.43	1890
HSA-MIR-4430	97.47	65.61	1813
HSA-MIR-4640-5P	97.42	66.33	1543
HSA-MIR-1291	96.28	65.89	1224

Literature-anchored findings (GeneRIF, showing 1)

• Prognostic and immune roles of UROC1 in human cancers: from mechanism exploration of NAFLD and HCC to pan-cancer analysis. (PMID:38305606)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	uroc1	ENSDARG00000070394
mus_musculus	Uroc1	ENSMUSG00000034456
rattus_norvegicus	Uroc1	ENSRNOG00000043404
caenorhabditis_elegans		WBGENE00013103

Protein

Protein identifiers

Urocanate hydratase — Q96N76 (reviewed: Q96N76)

Alternative names: Imidazolonepropionate hydrolase

All UniProt accessions (1): Q96N76

UniProt curated annotations — full annotation on UniProt →

Disease relevance. Urocanase deficiency (UROCD) [MIM:276880] An inborn error of histidine metabolism resulting in urocanic aciduria and neurological manifestations including intellectual disability, ataxia, episodic aggressive behavior or exaggerated affection-seeking. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Amino-acid degradation; L-histidine degradation into L-glutamate; N-formimidoyl-L-glutamate from L-histidine: step 2/3.

Similarity. Belongs to the urocanase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96N76-1	1	yes
Q96N76-2	2

RefSeq proteins (2): NP_001159446, NP_653240* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR023636	Urocanase_CS	Conserved_site
IPR023637	Urocanase-like	Family
IPR035085	Urocanase_Rossmann-like	Domain
IPR035400	Urocanase_N	Domain
IPR035401	Urocanase_C	Domain
IPR036190	Urocanase_sf	Homologous_superfamily
IPR038364	Urocanase_central_sf	Homologous_superfamily
IPR055351

Pfam: PF01175, PF17391, PF17392

Catalyzed reactions (Rhea), 1 shown:

• 4-imidazolone-5-propanoate = trans-urocanate + H2O (RHEA:13101)

UniProt features (17 total): binding site 9, sequence variant 5, chain 1, region of interest 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96N76-F1	95.68	0.90

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (9): 594; 126–127; 204; 251–253; 271; 317–318; 343–347; 354–355; 403

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-70921	Histidine catabolism

MSigDB gene sets: 103 (showing top): GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_GLUTAMATE_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, GOBP_GLUTAMINE_FAMILY_AMINO_ACID_METABOLIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, KEGG_HISTIDINE_METABOLISM, GOBP_AROMATIC_AMINO_ACID_METABOLIC_PROCESS, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_CATABOLIC_PROCESS, GOBP_AMINO_ACID_CATABOLIC_PROCESS, chr3q21

GO Biological Process (4): L-histidine catabolic process (GO:0006548), obsolete L-histidine catabolic process to glutamate and formamide (GO:0019556), obsolete L-histidine catabolic process to glutamate and formate (GO:0019557), obsolete L-histidine metabolic process (GO:0006547)

GO Molecular Function (3): urocanate hydratase activity (GO:0016153), protein binding (GO:0005515), lyase activity (GO:0016829)

GO Cellular Component (1): cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
aromatic amino acid catabolic process	1
imidazole-containing compound catabolic process	1
L-amino acid catabolic process	1
proteinogenic amino acid catabolic process	1
hydro-lyase activity	1
binding	1
catalytic activity	1
cytoplasm	1
cellular anatomical structure	1

Protein interactions and networks

STRING

834 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UROC1	HAL	P42357	984
UROC1	AMDHD1	Q96NU7	694
UROC1	FTCD	O95954	619
UROC1	GOLGA8M	H3BSY2	506
UROC1	TXNRD3	Q86VQ6	476
UROC1	SLC22A10	Q63ZE4	474
UROC1	CSAG1	Q6PB30	447
UROC1	GRIP2	Q9C0E4	425
UROC1	CSAG2	Q9Y5P2	417
UROC1	NOXRED1	Q6NXP6	392
UROC1	HGD	Q93099	368
UROC1	GFOD2	Q3B7J2	343
UROC1	SHPK	Q9UHJ6	339
UROC1	CHCHD4	Q8N4Q1	323
UROC1	SLC41A3	Q96GZ6	322

IntAct

5 interactions, top by confidence:

A	B	Type	Score
ALX1	UROC1	psi-mi:“MI:0915”(physical association)	0.560
ATG16L1		psi-mi:“MI:0914”(association)	0.350
UROC1	ALX1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (1): ALX1 (Two-hybrid)

ESM2 similar proteins: A0A5A4WIZ7, A1JT88, A1RL84, A1S4Y1, A3D311, A3QFX1, A4TSK9, A4Y5I7, A6H0N4, A6LV73, A6WLQ7, A7FPC3, A8H609, A9KD01, A9KWI3, A9NB02, A9R5S2, B1J2V6, B1JRQ0, B1KLT1, B2K867, B6J235, B6J5G0, B8CRF2, B8E5E3, B8F4B2, B8I4V6, C0QVH0, C5DA19, P00365, P50305, Q07ZY9, Q11W68, Q12LA9, Q1C0B2, Q1CCJ2, Q54VI3, Q5LDB2, Q663S5, Q6LP67

Diamond homologs: A0QRN3, A0RH38, A1JSW8, A1SQ09, A4FNF1, A4TS44, A4W8B4, A5F1X6, A5WA67, A6LP75, A6T6L0, A6VDL7, A7FP52, A7GQZ9, A7HN21, A7ZAE5, A8AJ16, A9MJF0, A9MTJ2, A9VPT7, B0KCB9, B0KM58, B0R541, B0V9X6, B0VPV2, B1J2Q5, B1JH60, B1VUR5, B2A3D8, B2I2C4, B2K6P6, B4REE0, B4SZJ3, B4TC44, B4TQT5, B5F068, B5QX61, B5XZ80, B7GUU5, B7HCC9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	132
Likely benign	42
Benign	11

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
3776010	NM_144639.3(UROC1):c.903-29del	Pathogenic
407	NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys)	Pathogenic
973479	NM_144639.3(UROC1):c.1448_1449del (p.Ser483fs)	Pathogenic

SpliceAI

3653 predictions. Top by Δscore:

Variant	Effect	Δscore
3:126482482:CCAC:C	acceptor_gain	1.0000
3:126482483:CAC:C	acceptor_gain	1.0000
3:126482483:CACC:C	acceptor_gain	1.0000
3:126482486:C:CG	acceptor_loss	1.0000
3:126483367:A:AC	donor_gain	1.0000
3:126483367:ACAC:A	donor_gain	1.0000
3:126483368:C:CC	donor_gain	1.0000
3:126483368:CA:C	donor_gain	1.0000
3:126483368:CACC:C	donor_gain	1.0000
3:126483368:CACCA:C	donor_gain	1.0000
3:126483464:CACCC:C	acceptor_gain	1.0000
3:126489269:T:TA	donor_gain	1.0000
3:126489270:CCTCA:C	donor_loss	1.0000
3:126489271:CTCA:C	donor_loss	1.0000
3:126489272:TCA:T	donor_loss	1.0000
3:126489273:CA:C	donor_loss	1.0000
3:126489275:C:CT	donor_loss	1.0000
3:126489373:CGC:C	acceptor_gain	1.0000
3:126489376:C:CC	acceptor_gain	1.0000
3:126489377:T:C	acceptor_loss	1.0000
3:126492412:CCTCA:C	donor_loss	1.0000
3:126492413:CTCA:C	donor_loss	1.0000
3:126492414:TCAC:T	donor_loss	1.0000
3:126492415:CAC:C	donor_loss	1.0000
3:126492416:ACCTT:A	donor_loss	1.0000
3:126492417:C:CA	donor_loss	1.0000
3:126496104:CTTCA:C	acceptor_gain	1.0000
3:126496105:TTCA:T	acceptor_gain	1.0000
3:126496106:TCA:T	acceptor_gain	1.0000
3:126496106:TCAC:T	acceptor_loss	1.0000

AlphaMissense

4438 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:126489317:C:A	R556M	0.999
3:126489325:G:C	S553R	0.999
3:126489325:G:T	S553R	0.999
3:126489327:T:G	S553R	0.999
3:126489337:G:C	S549R	0.999
3:126489337:G:T	S549R	0.999
3:126489339:T:G	S549R	0.999
3:126489349:G:C	H545Q	0.999
3:126489349:G:T	H545Q	0.999
3:126489351:G:C	H545D	0.999
3:126489353:T:A	D544V	0.999
3:126489353:T:G	D544A	0.999
3:126506002:C:A	Q204H	0.999
3:126506002:C:G	Q204H	0.999
3:126483453:G:C	N602K	0.998
3:126483453:G:T	N602K	0.998
3:126488213:C:T	G592E	0.998
3:126488215:G:C	N591K	0.998
3:126488215:G:T	N591K	0.998
3:126489317:C:G	R556T	0.998
3:126489348:G:C	H546D	0.998
3:126489352:A:C	D544E	0.998
3:126489352:A:T	D544E	0.998
3:126498138:A:G	W451R	0.998
3:126498138:A:T	W451R	0.998
3:126500085:A:C	N405K	0.998
3:126500085:A:T	N405K	0.998
3:126500089:C:A	G404V	0.998
3:126500801:G:C	H347D	0.998
3:126505755:A:C	S253R	0.998

dbSNP variants (sampled 300 via entrez): RS1000009902 (3:126503689 G>T), RS1000020258 (3:126494931 C>A,G,T), RS1000061005 (3:126509611 T>C,G), RS1000127943 (3:126514685 G>A), RS1000186563 (3:126498872 G>C,T), RS1000230454 (3:126489959 A>C,G), RS1000322733 (3:126498566 C>G), RS1000433485 (3:126514316 C>A,T), RS1000446203 (3:126503844 T>C), RS1000544297 (3:126488571 G>A), RS1000592379 (3:126498678 G>A), RS1000693718 (3:126509401 A>G), RS1000729056 (3:126509080 A>C), RS1000740816 (3:126513739 G>T), RS1000767932 (3:126493981 A>G,T)

Disease associations

OMIM: gene MIM:613012 | disease phenotypes: MIM:276880

GenCC curated gene-disease

Disease	Classification	Inheritance
urocanic aciduria	Moderate	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
urocanic aciduria	Limited	AR

Mondo (1): urocanic aciduria (MONDO:0010167)

Orphanet (1): Urocanic aciduria (Orphanet:210128)

HPO phenotypes

18 total (18 of 18 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000639	Nystagmus
HP:0000718	Aggressive behavior
HP:0001251	Ataxia
HP:0001260	Dysarthria
HP:0001310	Dysmetria
HP:0002066	Gait ataxia
HP:0002078	Truncal ataxia
HP:0002136	Broad-based gait
HP:0002342	Moderate intellectual disability
HP:0002345	Action tremor
HP:0002719	Recurrent infections
HP:0004322	Short stature
HP:0006801	Hyperactive deep tendon reflexes
HP:0007979	Gaze-evoked horizontal nystagmus
HP:0010904	Abnormal circulating histidine concentration
HP:0011463	Childhood onset
HP:0012237	Urocanic aciduria

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST003262_309	Post bronchodilator FEV1	3.000000e-07
GCST003902_2	Fast beta electroencephalogram	8.000000e-08
GCST006979_301	Heel bone mineral density	2.000000e-10
GCST007470_7	Rapid automatized naming of letters	7.000000e-07
GCST008159_7	Waist-to-hip ratio adjusted for BMI	9.000000e-06
GCST009203_1	Cerebellum cortex volume	6.000000e-06
GCST009515_1	Recurrence of malaria infection (mild or asymptomatic)	8.000000e-06
GCST010206_12	Anorectal malformation	6.000000e-10
GCST010726_21	Periventricular white matter hyperintensities	7.000000e-06

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004314	forced expiratory volume
EFO:0004357	electroencephalogram measurement
EFO:0007835	alcohol dependence measurement
EFO:0009270	heel bone mineral density
EFO:0005301	reading and spelling ability
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0004952	disease recurrence
EFO:0005665	white matter hyperintensity measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C536479	Urocanase deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

11 total (human), top 11 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation	4
methyleugenol	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
obeticholic acid	increases expression	1
Acetaminophen	decreases expression	1
DEET	decreases expression	1
Diazinon	increases methylation	1
Methapyrilene	increases methylation	1
N-Nitrosopyrrolidine	decreases expression	1
Aflatoxin B1	affects methylation, increases methylation	1

Clinical trials (associated diseases)

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