ZNRF3

protein-coding

zinc and ring finger 3, the group of Ring finger proteins

Gene summary

Enables frizzled binding activity and ubiquitin-protein transferase activity. Involved in negative regulation of Wnt signaling pathway; protein ubiquitination; and ubiquitin-dependent protein catabolic process. Located in plasma membrane. [provided by Alliance of Genome Resources, Jul 2025]

MANE transcript

NM_001206998.2

Inheritance

ClinVar variants

P:8U:148B:13

Top phenotype

complex neurodevelopmental disorder

gnomAD constraint

pLI —, LoF o/e 0.13

Max pathogenic AF

—

Genomic locus

chr22:28,883,572-29,057,488

External References & Databases

Ensembl (ENSG00000183579)

Transcript & Mutation Effects

hg38 • Region Span ~173.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: G2P

complex neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ZNRF3 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 122

not providedTotal: 21

ZNRF3-related disorderTotal: 12

ZNRF3-related conditionTotal: 1

ZNRF3-associated neurodevelopmental disorderTotal: 1

Male pseudohermaphroditismTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001206998.2. 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			2 clinvar	4 clinvar	2 clinvar	8
missense	7 clinvar	1 clinvar	132 clinvar	7 clinvar		147
nonsense			5 clinvar			5
start loss						0
frameshift			4 clinvar			4
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	7	1	148	11	2	169

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 23 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001206998.2	RefSeq	NP_001193927.1	9	MANE Select
ENST00000544604.7	Ensembl	ENSP00000443824.2	9	MANE Select
NM_032173.4	RefSeq	NP_115549.2	8	Standard
ENST00000402174.5	Ensembl	ENSP00000384456.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Signaling by WNT
Signal Transduction
Regulation of FZD by ubiquitination
TCF dependent signaling in response to WNT

Biological Process

ubiquitin-dependent protein catabolic process
Wnt signaling pathway
protein ubiquitination
Wnt receptor catabolic process
limb development

Molecular Function

ubiquitin-protein transferase activity
frizzled binding
protein binding
metal ion binding
ubiquitin protein ligase activity

Cellular Component

plasma membrane
integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000544604
Coding exons: 9
Length: 173896
Individuals with no LoFs: 124748
Homozygous LoFs: 0
Heterozygous LoFs: 47
Defined: 124795
p: 0.000188

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.975	482	546	0.883	0.0000357	5977
Missense (PolyPhen)		123	192.39	0.63933		2060
Synonymous	-1.97	280	241	1.16	0.0000170	1990
Loss of Function	4.51	4	31.2	0.128	0.00000163	357

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.00029	0.00016	rare
South Asian	0.0016	0.00088	notable
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of the Wnt signaling pathway by mediating the ubiquitination and subsequent degradation of Wnt receptor complex components Frizzled and LRP6. Acts on both canonical and non- canonical Wnt signaling pathway. Acts as a tumor suppressor in the intestinal stem cell zone by inhibiting the Wnt signaling pathway, thereby resticting the size of the intestinal stem cell zone. {ECO:0000269|PubMed:22575959}.;

Recessive Scores

pRec: 0.101

Intolerance Scores

LoFtool: 0.134
RVIS EVS: -0.11
RVIS percentile EVS: 45.49

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.764

Gene Damage Prediction

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