ZNRF4

Summary

ZNRF4 (zinc and ring finger 4, HGNC:17726) is a protein-coding gene on chromosome 19p13.3, encoding E3 ubiquitin-protein ligase ZNRF4 (Q8WWF5). E3 ubiquitin-protein ligase that acts as a negative regulator of NOD2 signaling by mediating ubiquitination and degradation of RIPK2.

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.

Source: NCBI Gene 148066 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 90 total
• MANE Select transcript: NM_181710

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17726
Approved symbol	ZNRF4
Name	zinc and ring finger 4
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	spzn, Ssrzf1, RNF204
Ensembl gene	ENSG00000105428
Ensembl biotype	protein_coding
OMIM	612063
Entrez	148066

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000222033

RefSeq mRNA: 1 — MANE Select: NM_181710 NM_181710

CCDS: CCDS42475

Canonical transcript exons

ENST00000222033 — 1 exons

Exon	Start	End
ENSE00000665652	5455417	5456856

Expression profiles

Bgee: expression breadth broad, 37 present calls, max score 95.74.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3300 / max 338.3137, expressed in 3 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
173409	0.2109	3
173410	0.1148	3
208660	0.0042	3

Top tissues by expression

244 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	95.74	gold quality
left testis	UBERON:0004533	95.52	gold quality
testis	UBERON:0000473	92.16	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.24	gold quality
triceps brachii	UBERON:0001509	85.14	gold quality
adult organism	UBERON:0007023	84.83	gold quality
type B pancreatic cell	CL:0000169	84.82	gold quality
gluteal muscle	UBERON:0002000	84.74	gold quality
olfactory bulb	UBERON:0002264	84.53	gold quality
tongue squamous epithelium	UBERON:0006919	82.16	gold quality
male germ cell	CL:0000015	81.20	silver quality
sperm	CL:0000019	80.18	silver quality
diaphragm	UBERON:0001103	80.00	gold quality
cervix squamous epithelium	UBERON:0006922	78.99	gold quality
vastus lateralis	UBERON:0001379	75.84	gold quality
nasal cavity epithelium	UBERON:0005384	75.51	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	75.32	gold quality
hair follicle	UBERON:0002073	75.31	gold quality
quadriceps femoris	UBERON:0001377	75.24	gold quality
biceps brachii	UBERON:0001507	73.57	gold quality
superficial temporal artery	UBERON:0001614	72.64	gold quality
CA1 field of hippocampus	UBERON:0003881	72.51	gold quality
mucosa of urinary bladder	UBERON:0001259	71.23	gold quality
thymus	UBERON:0002370	70.97	gold quality
tongue	UBERON:0001723	70.64	gold quality
lateral globus pallidus	UBERON:0002476	70.59	gold quality
vena cava	UBERON:0004087	70.49	gold quality
epithelial cell of pancreas	CL:0000083	70.36	gold quality
nipple	UBERON:0002030	70.32	gold quality
ventral tegmental area	UBERON:0002691	70.11	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.82

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 3)

• Characterization and study of mouse homolog. (PMID:10191088)
• Nixin/ZNRF4 to be central for the regulation of calnexin turnover. (PMID:21205830)
• ZNRF4 is a negative regulator of NOD2 and NF-kappaB. ZNRF4 promotes K48-linked ubiquitination of RIP2.ZNRF4 role in the protective host immunity. (PMID:28656966)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	rnf167	ENSDARG00000017636
mus_musculus	Znrf4	ENSMUSG00000044526
rattus_norvegicus	Znrf4	ENSRNOG00000048875

Paralogs (9): RNF13 (ENSG00000082996), RNF215 (ENSG00000099999), RNF167 (ENSG00000108523), RNF130 (ENSG00000113269), RNF128 (ENSG00000133135), RNF149 (ENSG00000163162), RNF150 (ENSG00000170153), RNF133 (ENSG00000188050), RNF148 (ENSG00000235631)

Protein

Protein identifiers

E3 ubiquitin-protein ligase ZNRF4 — Q8WWF5 (reviewed: Q8WWF5)

Alternative names: Nixin, RING finger protein 204, RING-type E3 ubiquitin transferase ZNRF4, Zinc/RING finger protein 4

All UniProt accessions (1): Q8WWF5

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase that acts as a negative regulator of NOD2 signaling by mediating ubiquitination and degradation of RIPK2. Also catalyzes ubiquitination and proteasomal degradation of CANX within the endoplasmic reticulum. Could have a role in spermatogenesis.

Subunit / interactions. Interacts with CANX.

Subcellular location. Endoplasmic reticulum membrane.

Domain organisation. The RING-type zinc finger is involved in CANX ubiquitination and degradation, but is not required for interaction with CANX.

Pathway. Protein modification; protein ubiquitination.

RefSeq proteins (1): NP_859061* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR003137	PA_domain	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR044744	ZNRF4/RNF13/RNF167_PA	Domain
IPR046450	PA_dom_sf	Homologous_superfamily
IPR051653	E3_ligase_sorting_rcpt	Family

Pfam: PF02225, PF13639

UniProt features (25 total): sequence variant 8, mutagenesis site 4, glycosylation site 3, topological domain 2, signal peptide 1, chain 1, sequence conflict 1, transmembrane region 1, domain 1, zinc finger region 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WWF5-F1	66.55	0.18

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Glycosylation sites (3): 152, 229, 107

Mutagenesis-validated functional residues (4):

Position	Phenotype
107	abolishes glycosylation; when associated with s-152 and s-229.
152	abolishes glycosylation; when associated with s-107 and s-229.
229	abolishes glycosylation; when associated with s-107 and s-152.
329–332	abolished e3 ubiquitin-protein ligase activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 79 (showing top): GOBP_NUCLEOTIDE_BINDING_DOMAIN_LEUCINE_RICH_REPEAT_CONTAINING_RECEPTOR_SIGNALING_PATHWAY, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, BROWNE_HCMV_INFECTION_48HR_DN, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE, GOBP_REGULATION_OF_CELL_CYCLE, BROWNE_HCMV_INFECTION_14HR_DN, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_INTRACELLULAR_RECEPTOR_SIGNALING_PATHWAY

GO Biological Process (8): ubiquitin-dependent protein catabolic process (GO:0006511), protein ubiquitination (GO:0016567), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), negative regulation of cell cycle (GO:0045786), negative regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway (GO:0070433), defense response to bacterium (GO:0042742), nucleotide-binding oligomerization domain containing 2 signaling pathway (GO:0070431), negative regulation of intracellular signal transduction (GO:1902532)

GO Molecular Function (5): zinc ion binding (GO:0008270), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (6): cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), endomembrane system (GO:0012505), membrane (GO:0016020), organelle membrane (GO:0031090)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein ubiquitination	1
modification-dependent protein catabolic process	1
protein modification by small protein conjugation	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
cell cycle	1
negative regulation of cellular process	1
regulation of cell cycle	1
negative regulation of nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway	1
nucleotide-binding oligomerization domain containing 2 signaling pathway	1
regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway	1
defense response	1
response to bacterium	1
nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway	1
negative regulation of signal transduction	1
intracellular signal transduction	1
regulation of intracellular signal transduction	1
transition metal ion binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
intracellular anatomical structure	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
vacuole	1
plasma membrane	1
membrane	1
membrane-bounded organelle	1

Protein interactions and networks

STRING

611 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZNRF4	PTPRS	Q13332	854
ZNRF4	RNF4	P78317	852
ZNRF4	GIPC3	Q8TF64	765
ZNRF4	ZNRF1	Q8ND25	600
ZNRF4	ZNRF2	Q8NHG8	595
ZNRF4	SAFB2	Q14151	589
ZNRF4	RNF170	Q96K19	566
ZNRF4	RNF103	O00237	538
ZNRF4	RNF175	Q8N4F7	499
ZNRF4	ERN1	O75460	480
ZNRF4	RNF139	Q8WU17	477
ZNRF4	RNF182	Q8N6D2	476
ZNRF4	RNF183	Q96D59	464
ZNRF4	RNF186	Q9NXI6	447
ZNRF4	RNF5	Q99942	429

IntAct

21 interactions, top by confidence:

A	B	Type	Score
TPRX1	ZNRF4	psi-mi:“MI:0915”(physical association)	0.560
NT5E	ZNRF4	psi-mi:“MI:0915”(physical association)	0.560
UPK2	ZNRF4	psi-mi:“MI:0915”(physical association)	0.560
ZNRF4	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
ZNRF4	UBE2D1	psi-mi:“MI:0915”(physical association)	0.370
UBE2D2	ZNRF4	psi-mi:“MI:0915”(physical association)	0.370
ZNRF4	UBE2D3	psi-mi:“MI:0915”(physical association)	0.370
UBE2D4	ZNRF4	psi-mi:“MI:0915”(physical association)	0.370
ZNRF4	UBE2E1	psi-mi:“MI:0915”(physical association)	0.370
ZNRF4	UBE2E3	psi-mi:“MI:0915”(physical association)	0.370
ZNRF4	UBE2G2	psi-mi:“MI:0915”(physical association)	0.370
UBE2N	ZNRF4	psi-mi:“MI:0915”(physical association)	0.370
UBE2W	ZNRF4	psi-mi:“MI:0915”(physical association)	0.370
NT5E	ZNRF4	psi-mi:“MI:0915”(physical association)	0.000
TPRX1	ZNRF4	psi-mi:“MI:0915”(physical association)	0.000
UPK2	ZNRF4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (179): UBA52 (Affinity Capture-MS), DAGLA (Affinity Capture-MS), ABCA2 (Affinity Capture-MS), AREL1 (Affinity Capture-MS), FZD6 (Affinity Capture-MS), PDZD8 (Affinity Capture-MS), KCNT2 (Affinity Capture-MS), KCNG1 (Affinity Capture-MS), ST7L (Affinity Capture-MS), ADCK2 (Affinity Capture-MS), C2CD2L (Affinity Capture-MS), TYW1 (Affinity Capture-MS), C1orf43 (Affinity Capture-MS), BTN2A2 (Affinity Capture-MS), OSBP (Affinity Capture-MS)

ESM2 similar proteins: A0A8M9QN10, A1BPI0, A2ARM1, A2CI97, A2CI98, A2CJ06, C9JE40, O15055, O43147, O54943, O70173, O70303, O70361, O95238, P0C2N6, P0C6P5, P56645, P59025, P59729, P97433, Q0P4K8, Q3TD16, Q5EB20, Q5PQS0, Q5SSZ5, Q5VUB5, Q6IRN0, Q6P4K6, Q76I79, Q7TSI1, Q80TQ5, Q80UW3, Q810F8, Q8C8C1, Q8CCC3, Q8CJE2, Q8N1W1, Q8ND61, Q8TB24, Q8WWF5

Diamond homologs: A5WWA0, E9QAU8, G3X9R7, O22197, O22755, O43567, O54965, O64763, P0C034, P0CH30, P0DPR2, Q06003, Q07G42, Q08D68, Q0II22, Q0VD51, Q10R93, Q14B02, Q29RU0, Q2TA44, Q3U2C5, Q4KLR8, Q4R6Y5, Q5NCP0, Q5RCV8, Q5RF74, Q5SPX3, Q5SSZ7, Q5XF85, Q641J8, Q66HG0, Q68DV7, Q69U49, Q6AY01, Q6DIP3, Q6IRP0, Q6NML0, Q6NQG7, Q6NRX0, Q6Y290

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	ZNRF4	ubiquitination
ZNRF4	“down-regulates quantity by destabilization”	RIPK2	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 13 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	6	200.9×	8e-12
E3 ubiquitin ligases ubiquitinate target proteins	5	88.0×	3e-08
Antigen processing: Ubiquitination & Proteasome degradation	9	30.4×	1e-11

GO biological processes:

GO term	Partners	Fold	FDR
protein monoubiquitination	5	143.3×	2e-09
protein K48-linked ubiquitination	7	98.3×	8e-12
protein polyubiquitination	7	67.3×	6e-11
ubiquitin-dependent protein catabolic process	6	37.1×	6e-08
protein ubiquitination	5	17.2×	4e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

90 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	86
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

66 predictions. Top by Δscore:

Variant	Effect	Δscore
19:5456443:G:GT	donor_gain	0.6000
19:5456431:GA:G	donor_gain	0.5700
19:5456432:A:G	donor_gain	0.5400
19:5456444:A:T	donor_gain	0.5300
19:5456430:GGA:G	donor_gain	0.5200
19:5456359:AAGAC:A	donor_gain	0.5000
19:5456436:G:GG	donor_gain	0.4700
19:5456432:A:AG	donor_gain	0.4600
19:5456285:T:TA	donor_gain	0.4500
19:5456357:TG:T	donor_gain	0.4200
19:5456435:A:AG	donor_gain	0.4000
19:5456602:G:T	donor_gain	0.3700
19:5455699:A:AG	donor_gain	0.3600
19:5456446:G:GT	donor_gain	0.3600
19:5455689:G:GT	donor_gain	0.3500
19:5455700:C:G	donor_gain	0.3500
19:5456127:GTTC:G	donor_gain	0.3500
19:5456180:A:G	donor_gain	0.3500
19:5456777:A:AG	donor_gain	0.3500
19:5456778:G:GG	donor_gain	0.3500
19:5456286:C:CA	donor_gain	0.3300
19:5456125:GT:G	donor_gain	0.3200
19:5456130:C:G	donor_gain	0.3100
19:5456131:G:GG	donor_gain	0.3100
19:5456182:T:TA	donor_gain	0.3100
19:5456516:A:AC	acceptor_gain	0.3100
19:5456601:G:GT	donor_gain	0.3100
19:5456095:G:GT	donor_gain	0.3000
19:5456183:C:A	donor_gain	0.2900
19:5456434:GA:G	donor_gain	0.2900

AlphaMissense

2741 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:5456004:G:C	K171N	0.989
19:5456004:G:T	K171N	0.989
19:5456029:T:C	F180L	0.988
19:5456031:C:A	F180L	0.988
19:5456031:C:G	F180L	0.988
19:5455993:T:C	F168L	0.985
19:5455995:C:A	F168L	0.985
19:5455995:C:G	F168L	0.985
19:5456128:T:C	F213L	0.981
19:5456130:C:A	F213L	0.981
19:5456130:C:G	F213L	0.981
19:5455849:T:C	F120L	0.975
19:5455851:C:A	F120L	0.975
19:5455851:C:G	F120L	0.975
19:5455994:T:G	F168C	0.959
19:5455828:T:C	F113L	0.957
19:5455830:T:A	F113L	0.957
19:5455830:T:G	F113L	0.957
19:5456052:C:A	N187K	0.955
19:5456052:C:G	N187K	0.955
19:5456019:G:C	Q176H	0.953
19:5456019:G:T	Q176H	0.953
19:5456395:T:C	F302L	0.951
19:5456397:C:A	F302L	0.951
19:5456397:C:G	F302L	0.951
19:5456487:C:A	H332Q	0.951
19:5456487:C:G	H332Q	0.951
19:5455850:T:G	F120C	0.947
19:5456042:T:A	I184N	0.947
19:5456051:A:T	N187I	0.947

dbSNP variants (sampled 300 via entrez): RS1000178560 (19:5457086 C>G,T), RS1000702079 (19:5454631 G>A), RS1001203018 (19:5453525 G>A), RS1001990788 (19:5453707 C>T), RS1002055242 (19:5454925 T>C), RS1002709334 (19:5457260 T>A,C), RS1002763349 (19:5457066 G>A), RS1002783888 (19:5453469 A>G), RS1004230541 (19:5456783 G>C,T), RS1004435067 (19:5455988 G>A), RS1004766062 (19:5455466 G>A,C), RS1006663292 (19:5457342 C>A,T), RS1006844379 (19:5454274 G>A), RS1007577749 (19:5454401 T>C,G), RS1011284970 (19:5454014 G>T)

Disease associations

OMIM: gene MIM:612063 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

10 total (human), top 10 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
perfluorooctanoic acid	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
perfluorohexanesulfonic acid	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Valproic Acid	increases methylation	1
Cadmium Chloride	increases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.