UROC1

protein-coding

urocanate hydratase 1

Gene summary

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. [provided by RefSeq, Apr 2021]

MANE transcript

NM_144639.3

Inheritance

ClinVar variants

P:4U:143B:55

Top phenotype

Urocanase deficiency

gnomAD constraint

pLI —, LoF o/e 0.72

Max pathogenic AF

—

Genomic locus

chr3:126,481,166-126,517,773

External References & Databases

Ensembl (ENSG00000159650)

Transcript & Mutation Effects

hg38 • Region Span ~36.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

urocanic aciduriaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0010167

Submitter: ClinGen

UROC1 was first reported in relation to autosomal recessive urocanic aciduria in 2009 (Espinos et al., PMID: 19304569), although association of the biochemical abnormality with the protein urocanase was characterized in 1971 (Yoshida et al., PMID: 5124677). There have been a variety of phenotypes reported in association with urocanic aciduria, including intellectual disability and developmental delay, however the relationship of these phenotypes to the biochemical abnormality is unclear. Four unique missense variants and one nonsense varaint have been reported in humans thus far. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in four probands in four separate publications (PMIDs: 19304569, 30619714, 32439973, 27391121). One family was asymptomatic except for the characteristic urocanic aciduria (PMID: 30619714). Segregation was observed and confirmed in one sibling in this family. The mechanism for disease is biallelic loss of function, with loss of enzyme activity resulting in a buildup of the prior metabolite in the histidine metabolic pathway, urocanic acid. This gene-disease association is additionally supported by unique expression in the human liver, correlating with the proposed pathogenic mechanism, and by the protein's function correlating with the resulting biochemical abnormality. However, the lack of any relevant animal models or functional data limits the conclusiveness of this evidence. In summary, there is Limited evidence to support this gene-disease relationship. Although more evidence, particularly observation in human probands and functional data, is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was originally approved by the Aminoacidopathy Gene Curation Expert Panel on November 13, 2020. This gene-disease relationship was re-evaluated on March 7, 2024. Two new patients with the NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) variant were added (PMIDs: 32439973, 27391121). It was again re-evaluated on April 10, 2026 with no evidence identified, maintaining the Limited classification.

urocanic aciduriaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0010167

Submitter: Labcorp Genetics (formerly Invitae)

urocanic aciduriaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010167

Submitter: Orphanet

urocanic aciduriaNO_KNOWN

Inheritance Pattern: AR

Disease ID:MONDO:0010167

Submitter: G2P

urocanic aciduriaMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0010167

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Urocanase deficiencyAR

Manifestation: Biochemical; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 5124677; 6107814; 19304569

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to UROC1 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 148

not providedTotal: 57

Urocanate hydratase deficiencyTotal: 14

UROC1-related disorderTotal: 11

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_144639.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	34 clinvar	3 clinvar	38
missense	1 clinvar		140 clinvar	14 clinvar	3 clinvar	158
nonsense		1 clinvar		1 clinvar		2
start loss						0
frameshift	1 clinvar					1
splice donor/acceptor (+/-2bp)		1 clinvar	2 clinvar			3
Total	2	2	143	49	6	202

Highest pathogenic variant AF is 0.00003159499

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_144639.3	RefSeq	NP_653240.1	20	MANE Select
ENST00000290868.7	Ensembl	ENSP00000290868.2	20	MANE Select
NM_001165974.2	RefSeq	NP_001159446.1	21	Standard
ENST00000383579.3	Ensembl	ENSP00000373073.3	21	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Histidine metabolism - Homo sapiens (human)
Histidine Metabolism
Histidinemia
Histidine catabolism
Histidine, lysine, phenylalanine, tyrosine, proline and tryptophan catabolism

Biological Process

histidine catabolic process
histidine catabolic process to glutamate and formamide
histidine catabolic process to glutamate and formate

Molecular Function

urocanate hydratase activity

Cellular Component

cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000383579
Coding exons: 21
Length: 36493
Individuals with no LoFs: 125444
Homozygous LoFs: 2
Heterozygous LoFs: 302
Defined: 125748
p: 0.00121

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.509	473	443	1.07	0.0000287	4774
Missense (PolyPhen)		274	252.57	1.0848		2707
Synonymous	-0.698	194	182	1.07	0.0000127	1462
Loss of Function	1.68	29	40.5	0.715	0.00000186	451

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0010	0.0010	notable
Latino/Admixed American	0.0011	0.0011	notable
Ashkenazi Jewish	0	0.0	absent
East Asian	0.011	0.011	notable
Finnish	0.000048	0.000046	rare
European (Non-Finnish)	0.00032	0.00032	rare
South Asian	0.00036	0.00036	rare
Other	0.00098	0.00098	rare

dbNSFP Gene Annotations

Source: dbNSFP

Disease: DISEASE: Urocanase deficiency (UROCD) [MIM:276880]: An inborn error of histidine metabolism resulting in urocanic aciduria and neurological manifestations including mental retardation, ataxia, episodic aggressive behavior or exaggerated affection-seeking. {ECO:0000269|PubMed:19304569}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.138

Intolerance Scores

LoFtool: 0.810
RVIS EVS: 0.32
RVIS percentile EVS: 72.83

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.887

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium