UGT1A8

protein-coding

UDP glucuronosyltransferase family 1 member A8, the group of UDP glucuronosyltransferases

Gene summary

This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. The enzyme encoded by this gene has glucuronidase activity with many substrates including coumarins, phenols, anthraquinones, flavones, and some opioids. [provided by RefSeq, Jul 2008]

MANE transcript

NM_019076.5

Inheritance

—

ClinVar variants

P:48U:119B:38

Top phenotype

Gilbert syndrome

gnomAD constraint

pLI —, LoF o/e 0.65

Max pathogenic AF

—

Genomic locus

chr2:233,617,633-233,773,300

External References & Databases

Ensembl (ENSG00000242366)

Transcript & Mutation Effects

hg38 • Region Span ~155.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to UGT1A8 variants in ClinVar

15 Conditions Cataloged

not specifiedTotal: 354

not providedTotal: 324

Gilbert syndromeTotal: 93

UGT1A1-related disorderTotal: 92

Lucey-Driscoll syndromeTotal: 77

Crigler-Najjar syndrome type 1Total: 65

Crigler-Najjar syndrome, type IITotal: 58

Crigler-Najjar syndromeTotal: 40

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_019076.5. 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			2 clinvar	32 clinvar	1 clinvar	35
missense	5 clinvar	19 clinvar	116 clinvar	5 clinvar		145
nonsense	4 clinvar	3 clinvar	1 clinvar			8
start loss						0
frameshift	6 clinvar	5 clinvar				11
splice donor/acceptor (+/-2bp)	2 clinvar	4 clinvar				6
Total	17	31	119	37	1	205

Highest pathogenic variant AF is 0.00048507

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_019076.5	RefSeq	NP_061949.3	5	MANE Select
ENST00000373450.5	Ensembl	ENSP00000362549.4	5	MANE Select
ENST00001023999.1	Ensembl	ENSP00000693816.1	5	Standard
ENST00001024000.1	Ensembl	ENSP00000693817.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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)

Biological Process

fatty acid metabolic process
steroid metabolic process
coumarin metabolic process
retinoic acid metabolic process
negative regulation of catalytic activity

Molecular Function

retinoic acid binding
enzyme inhibitor activity
steroid binding
fatty acid binding
UDP-glycosyltransferase activity

Cellular Component

endoplasmic reticulum
endoplasmic reticulum membrane
integral component of membrane
intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000305208
Coding exons: 5
Length: 13052
Individuals with no LoFs: 125699
Homozygous LoFs: 0
Heterozygous LoFs: 49
Defined: 125748
p: 0.000195

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.247	309	297	1.04	0.0000175	3498
Missense (PolyPhen)		131	129.52	1.0114		1493
Synonymous	-0.219	126	123	1.03	0.00000800	1084
Loss of Function	1.32	11	16.9	0.653	8.19e-7	203

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00021	0.00020	rare
South Asian	0.00056	0.00056	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. Isoform 2 lacks transferase activity but acts as a negative regulator of isoform 1. {ECO:0000269|PubMed:19545173}.;

Recessive Scores

pRec: 0.581

Intolerance Scores

RVIS EVS: -0.42
RVIS percentile EVS: 25.73

Essentials

Essential (CRISPR): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0701