UGT1A1

UDP glucuronosyltransferase family 1 member A1, the group of UDP glucuronosyltransferases

Basic information

Region (hg38): 2:233760270-233773300

Previous symbols: [ "UGT1", "GNT1" ]

Links

ENSG00000241635 ∙ NCBI:54658 ∙ OMIM:191740 ∙ HGNC:12530 ∙ Uniprot:P22309 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Crigler-Najjar syndrome type 1 (Definitive), mode of inheritance: AR
• Crigler-Najjar syndrome type 1 (Supportive), mode of inheritance: AR
• Crigler-Najjar syndrome type 2 (Supportive), mode of inheritance: AR
• Gilbert syndrome (Strong), mode of inheritance: AR
• Crigler-Najjar syndrome type 1 (Definitive), mode of inheritance: AR
• Crigler-Najjar syndrome type 2 (Definitive), mode of inheritance: AR
• Crigler-Najjar syndrome type 1 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Crigler-Najjar syndrome, type I; Crigler-Najjar syndrome, type II; Gilbert syndrome	AD/AR	Gastrointestinal; Pharmacogenomic	In CNI, phototherapy (or other interventions, such as plasmapharesis), followed by liver transplantation may be beneficial; In CNII, not all individuals have severe forms of disease necessitating treatment, but patients with severe forms typically respond to phenobarbital treatment; Knowledge of the cause of jaundice even in less severe cases can help avoid prolonged etiologic work-ups; While Gilbert syndrome is not as severe as other disorders of hyperbilirubinemia, drug metabolism related to certain medications (eg, acetaminophen, atazanavir, irinotecan) imay be affected, and medication and dosing choice may be beneficial	Gastrointestinal	12983120; 5685361; 805737; 3546653; 1734381; 1531971; 8276413; 7989595; 7565971; 8528206; 8690398; 9413009; 9580649; 9621515; 10412811; 11003624; 11061796; 11316168; 11370628; 11906189; 16712705; 18518849; 22676194; 22710376; 23099197; 23162302; 23241680; 23279026; 23403257; 23430851; 23926009; 23992562; 24065680

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the UGT1A1 gene.

• not provided (22 variants)
• Crigler-Najjar syndrome type 1 (6 variants)
• Crigler-Najjar syndrome (4 variants)
• UGT1A1-related disorder (3 variants)
• Hyperbilirubinemia (2 variants)
• Gilbert syndrome (2 variants)
• Crigler-Najjar syndrome, type II (2 variants)
• Crigler-Najjar syndrome type 1;Gilbert syndrome;Crigler-Najjar syndrome, type II;Lucey-Driscoll syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the UGT1A1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			12	33		45
missense	4	13	115			132
nonsense	5		3			8
start loss		1				1
frameshift	13	5				18
inframe indel	1	1	3			5
splice donor/acceptor (+/-2bp)	2	3				5
splice region			2	1		3
non coding			11	6	10	27
Total	25	23	144	39	10

Highest pathogenic variant AF is 0.0000919

Variants in UGT1A1

This is a list of pathogenic ClinVar variants found in the UGT1A1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
2-233760284-C-T		UGT1A4-related disorder	Uncertain significance (May 15, 2018)
2-233760285-GCCATGGCTGTGGAGTC-G		Gilbert syndrome	Likely pathogenic (Aug 01, 2021)
2-233760306-G-A			Uncertain significance (Mar 07, 2017)
2-233760308-C-T		UGT1A1-related disorder	Likely benign (Apr 29, 2020)
2-233760309-G-A		Inborn genetic diseases	Conflicting classifications of pathogenicity (Dec 15, 2023)
2-233760312-C-T		Gilbert syndrome • Lucey-Driscoll syndrome • Crigler-Najjar syndrome	Uncertain significance (Jan 13, 2018)
2-233760323-C-T			Likely benign (Dec 02, 2021)
2-233760331-T-G		Crigler-Najjar syndrome, type II • Gilbert syndrome;Bilirubin, serum level of, quantitative trait locus 1;Crigler-Najjar syndrome, type II;Lucey-Driscoll syndrome;Crigler-Najjar syndrome type 1	Likely pathogenic (Jul 28, 2021)
2-233760332-G-C		UGT1A1-related disorder	Likely benign (Mar 04, 2021)
2-233760344-G-A		UGT1A1-related disorder	Likely benign (Mar 31, 2022)
2-233760358-T-TG			Pathogenic (Dec 02, 2021)
2-233760359-G-A		not specified • Lucey-Driscoll syndrome;Crigler-Najjar syndrome, type II;Bilirubin, serum level of, quantitative trait locus 1;Crigler-Najjar syndrome type 1;Gilbert syndrome • UGT1A1-related disorder	Likely benign (Jan 17, 2022)
2-233760364-ATGCTGGGAAGATAC-A		UGT1A1-related disorder	Pathogenic/Likely pathogenic (Nov 10, 2023)
2-233760365-T-C		UGT1A1-related disorder	Likely benign (Feb 17, 2022)
2-233760376-T-C		UGT1A1-related disorder	Uncertain significance (May 18, 2023)
2-233760379-T-G		Crigler-Najjar syndrome type 1	Uncertain significance (-)
2-233760394-A-G			Uncertain significance (Jun 30, 2022)
2-233760397-G-A		Crigler-Najjar syndrome, type II	Uncertain significance (-)
2-233760397-G-T			Uncertain significance (Mar 01, 2023)
2-233760398-C-A			Likely benign (Jan 12, 2022)
2-233760405-T-C			Uncertain significance (Jan 06, 2023)
2-233760412-G-A		UGT1A1-related disorder	Uncertain significance (Feb 22, 2024)
2-233760418-T-A			Uncertain significance (Jun 12, 2023)
2-233760424-C-T		Lucey-Driscoll syndrome;Crigler-Najjar syndrome, type II;Gilbert syndrome;Crigler-Najjar syndrome type 1;Bilirubin, serum level of, quantitative trait locus 1	Uncertain significance (Mar 10, 2022)
2-233760425-C-T			Uncertain significance (Aug 11, 2016)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
UGT1A1	protein_coding	protein_coding	ENST00000609767	5	155666

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.31e-9	0.196	125278	2	468	125748	0.00187

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-1.35	360	295	1.22	0.0000166	3508
Missense in Polyphen		146	141.4	1.0325		1691
Synonymous	-2.82	157	118	1.33	0.00000713	1068
Loss of Function	0.523	15	17.4	0.864	9.31e-7	204

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0139	0.0139
Ashkenazi Jewish	0.00596	0.00587
East Asian	0.000163	0.000163
Finnish	0.00111	0.00111
European (Non-Finnish)	0.000962	0.000959
Middle Eastern	0.000163	0.000163
South Asian	0.000556	0.000523
Other	0.00179	0.00179

dbNSFP

Source: dbNSFP

• Function: FUNCTION: UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX- alpha to form both the IX-alpha-C8 and IX-alpha-C12 monoconjugates and diconjugate. Is also able to catalyze the glucuronidation of 17beta-estradiol, 17alpha-ethinylestradiol, 1-hydroxypyrene, 4- methylumbelliferone, 1-naphthol, paranitrophenol, scopoletin, and umbelliferone. Isoform 2 lacks transferase activity but acts as a negative regulator of isoform 1. {ECO:0000269|PubMed:18004206, ECO:0000269|PubMed:19545173, ECO:0000269|PubMed:19830808}.
• Disease: DISEASE: Gilbert syndrome (GILBS) [MIM:143500]: Occurs as a consequence of reduced bilirubin transferase activity and is often detected in young adults with vague non-specific complaints. {ECO:0000269|PubMed:11013440, ECO:0000269|PubMed:12139570, ECO:0000269|PubMed:7715297, ECO:0000269|PubMed:9627603}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Transient familial neonatal hyperbilirubinemia (HBLRTFN) [MIM:237900]: A condition characterized by excessive concentration of bilirubin in the blood, which may lead to jaundice. Breast milk jaundice is a common problem in nursing infants. {ECO:0000269|PubMed:11061796}. Note=The disease may be caused by mutations affecting the gene represented in this entry. The defect has been ascribed to various breast milk substances, but the component or combination of components that is responsible remains unclear. Defects of UGT1A1 are an underlying cause of the prolonged unconjugated hyperbilirubinemia associated with breast milk. One or more components in the milk may trigger the jaundice in infants who have such mutations. Mutations are identical to those detected in patients with Gilbert syndrome, a risk factor of neonatal non-physiologic hyperbilirubinemia and a genetic factor in fasting hyperbilirubinemia.; DISEASE: Crigler-Najjar syndrome 1 (CN1) [MIM:218800]: Patients have severe hyperbilirubinemia and usually die of kernicterus (bilirubin accumulation in the basal ganglia and brainstem nuclei) within the first year of life. CN1 inheritance is autosomal recessive. {ECO:0000269|PubMed:11013440, ECO:0000269|PubMed:15712364, ECO:0000269|PubMed:1634050, ECO:0000269|PubMed:17229650, ECO:0000269|PubMed:19830808, ECO:0000269|PubMed:23992562, ECO:0000269|PubMed:7906695, ECO:0000269|PubMed:7989045, ECO:0000269|PubMed:7989595, ECO:0000269|PubMed:8226884}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Crigler-Najjar syndrome 2 (CN2) [MIM:606785]: Patients have less severe hyperbilirubinemia and usually survive into adulthood without neurologic damage. Phenobarbital, which induces the partially deficient glucuronyl transferase, can diminish the jaundice. CN2 inheritance is autosomal dominant. {ECO:0000269|PubMed:11013440, ECO:0000269|PubMed:11370628, ECO:0000269|PubMed:12402338, ECO:0000269|PubMed:14550264, ECO:0000269|PubMed:15712364, ECO:0000269|PubMed:17229650, ECO:0000269|PubMed:18004206, ECO:0000269|PubMed:19830808, ECO:0000269|PubMed:23099197, ECO:0000269|PubMed:23992562, ECO:0000269|PubMed:7989595, ECO:0000269|PubMed:8276413, ECO:0000269|PubMed:8280139, ECO:0000269|PubMed:8706880, ECO:0000269|PubMed:9621515, ECO:0000269|PubMed:9639672}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Retinol metabolism - Homo sapiens (human);Steroid hormone biosynthesis - Homo sapiens (human);Metabolism of xenobiotics by cytochrome P450 - Homo sapiens (human);Drug metabolism - other enzymes - Homo sapiens (human);Drug metabolism - cytochrome P450 - Homo sapiens (human);Porphyrin and chlorophyll metabolism - Homo sapiens (human);Chemical carcinogenesis - Homo sapiens (human);Ascorbate and aldarate metabolism - Homo sapiens (human);Pentose and glucuronate interconversions - Homo sapiens (human);Losartan Pathway, Pharmacokinetics;Statin Pathway - Generalized, Pharmacokinetics;Atorvastatin/Lovastatin/Simvastatin Pathway, Pharmacokinetics;Fluvastatin Pathway, Pharmacokinetics;Phenytoin Pathway, Pharmacokinetics;Estrogen Metabolism Pathway;Codeine and Morphine Pathway, Pharmacokinetics;Erlotinib Pathway, Pharmacokinetics;Sorafenib Pharmacokinetics;Pathway_PA165986194 -need delete;Acetaminophen Pathway, Pharmacokinetics;Irinotecan Pathway, Pharmacokinetics;Etoposide Pathway, Pharmacokinetics/Pharmacodynamics;Irinotecan Pathway, Pharmacodynamics;Ibuprofen Action Pathway;Phenytoin (Antiarrhythmic) Action Pathway;Ibuprofen Metabolism Pathway;Morphine Metabolism Pathway;Irinotecan Action Pathway;Morphine Action Pathway;Etoposide Action Pathway;Sorafenib Metabolism Pathway;Acetaminophen Metabolism Pathway;Vitamin A Deficiency;Irinotecan Metabolism Pathway;Etoposide Metabolism Pathway;Retinol Metabolism;Codeine and Morphine Metabolism;Irinotecan Pathway;Aryl Hydrocarbon Receptor Pathway;Constitutive Androstane Receptor Pathway;Pregnane X Receptor pathway;Nuclear Receptors Meta-Pathway;NRF2 pathway;Liver steatosis AOP;Estrogen metabolism;Glucuronidation;Metapathway biotransformation Phase I and II;Glucuronidation;Phase II - Conjugation of compounds;Heme degradation;Metabolism of porphyrins;Tyrosine metabolism;Androgen and estrogen biosynthesis and metabolism;Biological oxidations;Metabolism;Linoleate metabolism;Vitamin A (retinol) metabolism;Xenobiotics metabolism;Porphyrin metabolism (Consensus)

Recessive Scores

• pRec: 0.581

Intolerance Scores

• loftool: 0.881
• rvis_EVS: -0.56
• rvis_percentile_EVS: 19.73

Haploinsufficiency Scores

• hipred: N
• hipred_score: 0.131

Essentials

• essential_gene_CRISPR: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.0320

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Ugt1a1

Gene ontology

• Biological process: liver development;bilirubin conjugation;acute-phase response;response to nutrient;steroid metabolic process;estrogen metabolic process;drug metabolic process;animal organ regeneration;response to lipopolysaccharide;heme catabolic process;retinoic acid metabolic process;response to starvation;negative regulation of catalytic activity;negative regulation of steroid metabolic process;heterocycle metabolic process;flavone metabolic process;cellular glucuronidation;flavonoid glucuronidation;xenobiotic glucuronidation;biphenyl catabolic process;cellular response to ethanol;cellular response to glucocorticoid stimulus;cellular response to estradiol stimulus
• Cellular component: endoplasmic reticulum;endoplasmic reticulum membrane;integral component of plasma membrane;endoplasmic reticulum chaperone complex;intracellular membrane-bounded organelle;cytochrome complex
• Molecular function: retinoic acid binding;enzyme inhibitor activity;steroid binding;UDP-glycosyltransferase activity;glucuronosyltransferase activity;enzyme binding;protein homodimerization activity;protein heterodimerization activity