GeneBe

FZR1

protein-coding

fizzy and cell division cycle 20 related 1, the group of WD repeat domain containing

Gene summary

Enables ubiquitin-like ligase-substrate adaptor activity. Involved in anaphase-promoting complex-dependent catabolic process; mitotic G2 DNA damage checkpoint signaling; and positive regulation of ubiquitin protein ligase activity. Located in nuclear membrane and nucleoplasm. Implicated in developmental and epileptic encephalopathy 109. [provided by Alliance of Genome Resources, Jul 2025]

MANE transcript

NM_016263.4

Inheritance

AD

ClinVar variants

P:5U:66B:14

Top phenotype

developmental and epileptic encephalopathy 109

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chr19:3,506,311-3,538,334

External References & Databases

Ensembl (ENSG00000105325)NCBI Gene (51343)OMIM (603619)HGNC:24824GenCCUniProt (Q9UM11)AlphaFoldClinVar (FZR1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~32.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental and epileptic encephalopathy 109STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859325

Submitter: G2P

developmental and epileptic encephalopathy 109STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859325

Submitter: Labcorp Genetics (formerly Invitae)

developmental and epileptic encephalopathy 109STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859325

Submitter: PanelApp Australia

developmental and epileptic encephalopathy 109MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0859325

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FZR1 variants in ClinVar

10 Conditions Cataloged
Inborn genetic diseasesTotal: 45
not providedTotal: 21
Developmental and epileptic encephalopathy 109Total: 11
FZR1-related conditionTotal: 8
not specifiedTotal: 2
Cerebellar ataxiaTotal: 1
AutismTotal: 1
HypotoniaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016263.4. 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.

EffectPLPVUSLBBSum
synonymous
4
clinvar
8
clinvar
3
clinvar
 15
missense
3
clinvar
2
clinvar
55
clinvar
3
clinvar
 63
nonsense
1
clinvar
 1
start loss
0
frameshift
1
clinvar
 1
splice donor/acceptor (+/-2bp)
5
clinvar
 5
Total326611385
Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 48 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_016263.4RefSeqNP_057347.213MANE Select
ENST00000441788.7EnsemblENSP00000410369.113MANE Select
NM_001136197.1RefSeqNP_001129669.111Standard
NM_001136198.1RefSeqNP_001129670.113Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
fzr1aDanio rerio

Structure: lens

Quality: mislocalised anteriorly

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Cell cycle - Homo sapiens (human)
  • Ubiquitin mediated proteolysis - Homo sapiens (human)
  • Progesterone-mediated oocyte maturation - Homo sapiens (human)
  • Senescence-Associated Secretory Phenotype (SASP)
  • Cellular Senescence

Biological Process

  • DNA repair
  • cell cycle
  • positive regulation of cell population proliferation
  • anaphase-promoting complex-dependent catabolic process
  • regulation of meiotic nuclear division

Molecular Function

  • protein binding
  • anaphase-promoting complex binding
  • ubiquitin-protein transferase activator activity

Cellular Component

  • nucleoplasm
  • anaphase-promoting complex
  • cytosol
  • nuclear membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000395095
Coding exons
13
Length
32058
Individuals with no LoFs
124307
Homozygous LoFs
0
Heterozygous LoFs
1
Defined
124308
p
0.00000402
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense3.641433290.4350.00002293173
Missense (PolyPhen)26129.580.200651187
Synonymous-0.6021591501.060.00001121017
Loss of Function4.69127.60.03630.00000138285

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian0.0000550.000055rare
Finnish00.0absent
European (Non-Finnish)00.0absent
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Substrate-specific adapter for the anaphase promoting complex/cyclosome (APC/C) E3 ubiquitin-protein ligase complex. Associates with the APC/C in late mitosis, in replacement of CDC20, and activates the APC/C during anaphase and telophase. The APC/C remains active in degrading substrates to ensure that positive regulators of the cell cycle do not accumulate prematurely. At the G1/S transition FZR1 is phosphorylated, leading to its dissociation from the APC/C. Following DNA damage, it is required for the G2 DNA damage checkpoint: its dephosphorylation and reassociation with the APC/C leads to the ubiquitination of PLK1, preventing entry into mitosis. Acts as an adapter for APC/C to target the DNA-end resection factor RBBP8/CtIP for ubiquitination and subsequent proteasomal degradation. Through the regulation of RBBP8/CtIP protein turnover, may play a role in DNA damage response, favoring DNA double-strand repair through error-prone non-homologous end joining (NHEJ) over error-free, RBBP8-mediated homologous recombination (HR) (PubMed:25349192). {ECO:0000269|PubMed:18662541, ECO:0000269|PubMed:21596315, ECO:0000269|PubMed:25349192, ECO:0000269|PubMed:9734353}.;

Recessive Scores

pRec
0.136

Intolerance Scores

LoFtool
0.0431
RVIS EVS
-0.8
RVIS percentile EVS
12.24

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.902

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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