RNF146

protein-coding

ring finger protein 146, the group of Ring finger proteins

Gene summary

Enables poly-ADP-D-ribose binding activity and ubiquitin-protein transferase activity. Involved in positive regulation of canonical Wnt signaling pathway; protein ubiquitination; and ubiquitin-dependent protein catabolic process. Located in cytosol and plasma membrane. [provided by Alliance of Genome Resources, Jun 2026]

MANE transcript

NM_001242850.2

Inheritance

—

ClinVar variants

U:42B:3

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.14

Max pathogenic AF

—

Genomic locus

chr6:127,266,726-127,288,567

External References & Databases

Ensembl (ENSG00000118518)

Transcript & Mutation Effects

hg38 • Region Span ~21.8 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 RNF146 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 43

not providedTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001242850.2. 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		1
missense			42 clinvar	1 clinvar	1 clinvar	44
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	42	2	1	45

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 41 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001242850.2	RefSeq	NP_001229779.1	2	MANE Select
ENST00000368314.6	Ensembl	ENSP00000357297.1	2	MANE Select
NM_001242844.2	RefSeq	NP_001229773.1	1	Standard
NM_001242845.2	RefSeq	NP_001229774.1	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Signaling by WNT
Signal Transduction
Regulation of PTEN stability and activity
Post-translational protein modification
Metabolism of proteins

Biological Process

ubiquitin-dependent protein catabolic process
Wnt signaling pathway
protein autoubiquitination
protein K48-linked ubiquitination
positive regulation of canonical Wnt signaling pathway

Molecular Function

ubiquitin-protein transferase activity
protein binding
zinc ion binding
ubiquitin protein ligase activity
poly-ADP-D-ribose binding

Cellular Component

nucleoplasm
cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000368314
Coding exons: 2
Length: 21958
Individuals with no LoFs: 125505
Homozygous LoFs: 0
Heterozygous LoFs: 9
Defined: 125514
p: 0.0000359

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.33	148	201	0.736	0.0000106	2311
Missense (PolyPhen)		32	74.975	0.42681		856
Synonymous	0.384	71	75.2	0.944	0.00000421	750
Loss of Function	3.03	2	14.4	0.139	9.61e-7	155

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000063	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000036	0.000035	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: E3 ubiquitin-protein ligase that specifically binds poly-ADP-ribosylated (PARsylated) proteins and mediates their ubiquitination and subsequent degradation. May regulate many important biological processes, such as cell survival and DNA damage response. Acts as an activator of the Wnt signaling pathway by mediating the ubiquitination of PARsylated AXIN1 and AXIN2, 2 key components of the beta-catenin destruction complex. Acts in cooperation with tankyrase proteins (TNKS and TNKS2), which mediate PARsylation of target proteins AXIN1, AXIN2, BLZF1, CASC3, TNKS and TNKS2. Recognizes and binds tankyrase-dependent PARsylated proteins via its WWE domain and mediates their ubiquitination, leading to their degradation. Different ubiquitin linkage types have been observed: TNKS2 undergoes ubiquitination at 'Lys-48' and 'Lys-63', while AXIN1 is only ubiquitinated at 'Lys-48'. May regulate TNKS and TNKS2 subcellular location, preventing aggregation at a centrosomal location. Neuroprotective protein. Protects the brain against N-methyl-D-aspartate (NMDA) receptor-mediated glutamate excitotoxicity and ischemia, by interfering with PAR-induced cell death, called parthanatos. Prevents nuclear translocation of AIFM1 in a PAR-binding dependent manner. Does not affect PARP1 activation (By similarity). Protects against cell death induced by DNA damaging agents, such as N- methyl-N-nitro-N-nitrosoguanidine (MNNG) and rescues cells from G1 arrest. Promotes cell survival after gamma-irradiation. Facilitates DNA repair. {ECO:0000250, ECO:0000269|PubMed:21478859, ECO:0000269|PubMed:21602803, ECO:0000269|PubMed:21799911, ECO:0000269|PubMed:21825151, ECO:0000269|PubMed:22267412}.;
Disease: DISEASE: Note=Defects in RNF146 are a cause of susceptibility to breast cancer.;

Recessive Scores

pRec: 0.0731

Intolerance Scores

LoFtool: 0.402
RVIS EVS: 0.15
RVIS percentile EVS: 64.51

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.539

Gene Damage Prediction

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