ARIH1

protein-coding

ariadne RBR E3 ubiquitin protein ligase 1, the group of RBR E3 ubiquitin ligases

Gene summary

Enables enzyme binding activity; ubiquitin-protein transferase activity; and zinc ion binding activity. Involved in protein ubiquitination. Located in several cellular components, including Lewy body; cullin-RING ubiquitin ligase complex; and nuclear body. [provided by Alliance of Genome Resources, Jul 2025]

MANE transcript

NM_005744.5

Inheritance

ClinVar variants

U:100B:86

Top phenotype

thoracic aortic aneurysm

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chr15:72,474,330-72,602,987

External References & Databases

Ensembl (ENSG00000166233)

Transcript & Mutation Effects

hg38 • Region Span ~128.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

thoracic aortic aneurysmSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0005396

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ARIH1 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 269

not specifiedTotal: 25

ARIH1-related disorderTotal: 10

Familial thoracic aortic aneurysm and aortic dissectionTotal: 3

Aortic aneurysmTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005744.5. 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			1 clinvar	83 clinvar	3 clinvar	87
missense			96 clinvar			96
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	0	100	83	3	186

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 25 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005744.5	RefSeq	NP_005735.2	14	MANE Select
ENST00000379887.9	Ensembl	ENSP00000369217.4	14	MANE Select
ENST00000561770.1	Ensembl	ENSP00000457767.1	2	Standard
ENST00000562891.2	Ensembl	ENSP00000477687.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cytokine Signaling in Immune system
Immune System
ISG15 antiviral mechanism
Antiviral mechanism by IFN-stimulated genes
Interferon Signaling

Biological Process

protein polyubiquitination
ubiquitin-dependent protein catabolic process
protein ubiquitination
positive regulation of proteasomal ubiquitin-dependent protein catabolic process

Molecular Function

ubiquitin-protein transferase activity
protein binding
zinc ion binding
ubiquitin-like protein transferase activity
ubiquitin conjugating enzyme binding

Cellular Component

ubiquitin ligase complex
cytoplasm
cytosol
Cajal body
nuclear body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000379887
Coding exons: 14
Length: 113026
Individuals with no LoFs: 125731
Homozygous LoFs: 0
Heterozygous LoFs: 6
Defined: 125737
p: 0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.59	74	297	0.250	0.0000150	3718
Missense (PolyPhen)		6	98.022	0.061211		1266
Synonymous	0.307	97	101	0.961	0.00000483	932
Loss of Function	5.40	2	37.9	0.0528	0.00000209	412

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: E3 ubiquitin-protein ligase, which catalyzes ubiquitination of target proteins together with ubiquitin- conjugating enzyme E2 UBE2L3 (PubMed:15236971, PubMed:21532592, PubMed:24076655, PubMed:27565346, PubMed:23707686). Acts as an atypical E3 ubiquitin-protein ligase by working together with cullin-RING ubiquitin ligase (CRL) complexes and initiating ubiquitination of CRL substrates: associates with CRL complexes and specifically mediates addition of the first ubiquitin on CRLs targets (PubMed:27565346). The initial ubiquitin is then elongated by CDC34/UBE2R1 and UBE2R2 (PubMed:27565346). E3 ubiquitin-protein ligase activity is activated upon binding to neddylated cullin- RING ubiquitin ligase complexes (PubMed:24076655, PubMed:27565346). Plays a role in protein translation in response to DNA damage by mediating ubiquitination of EIF4E2, the consequences of EIF4E2 ubiquitination are however unclear (PubMed:25624349). According to a report, EIF4E2 ubiquitination leads to promote EIF4E2 cap-binding and protein translation arrest (PubMed:25624349). According to another report EIF4E2 ubiquitination leads to its subsequent degradation (PubMed:14623119). Acts as the ligase involved in ISGylation of EIF4E2 (PubMed:17289916). {ECO:0000269|PubMed:14623119, ECO:0000269|PubMed:15236971, ECO:0000269|PubMed:17289916, ECO:0000269|PubMed:21532592, ECO:0000269|PubMed:23707686, ECO:0000269|PubMed:24076655, ECO:0000269|PubMed:25624349, ECO:0000269|PubMed:27565346}.;

Intolerance Scores

LoFtool: 0.0347
RVIS EVS: -0.14
RVIS percentile EVS: 42.88

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.966

Gene Damage Prediction

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