ZNRF4

protein-coding

zinc and ring finger 4, the group of Ring finger proteins

Gene summary

Enables ubiquitin protein ligase activity. Involved in negative regulation of nucleotide-binding activity oligomerization domain containing 2 signaling pathway and proteasome-mediated ubiquitin-dependent protein catabolic process. Is active in endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Jul 2025]

MANE transcript

NM_181710.4

Inheritance

—

ClinVar variants

U:86B:4

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr19:5,455,417-5,456,856

External References & Databases

Ensembl (ENSG00000105428)

Transcript & Mutation Effects

hg38 • Region Span ~1.4 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 ZNRF4 variants in ClinVar

1 Conditions Cataloged

not specifiedTotal: 90

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_181710.4. 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						0
missense			86 clinvar	4 clinvar		90
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	86	4	0	90

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_181710.4	RefSeq	NP_859061.3	1	MANE Select
ENST00000222033.6	Ensembl	ENSP00000222033.4	1	MANE Select

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

ubiquitin-dependent protein catabolic process
protein ubiquitination

Molecular Function

protein binding
metal ion binding
ubiquitin protein ligase activity

Cellular Component

endoplasmic reticulum membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000222033
Coding exons: 1
Length: 1442
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.245	280	292	0.960	0.0000218	2671
Missense (PolyPhen)		55	68.564	0.80217		671
Synonymous	-1.11	158	141	1.12	0.0000118	945
Loss of Function	1.26	0	1.84	0.00	7.93e-8	18

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	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: E3 ubiquitin-protein ligase which specifically induces ubiquitination and proteasomal degradation of CANX within the endoplasmic reticulum (PubMed:21205830). Could have a role in spermatogenesis (By similarity). {ECO:0000250|UniProtKB:Q9DAH2, ECO:0000269|PubMed:21205830}.;

Recessive Scores

pRec: 0.0972

Intolerance Scores

LoFtool: 0.465
RVIS EVS: 1.65
RVIS percentile EVS: 96.21

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.246

Gene Damage Prediction

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