FZR1

Chr 19AD

fizzy and cell division cycle 20 related 1

Also known as: CDC20C, CDH1, DEE109, FZR, FZR2, HCDH, HCDH1

NCBI Gene: 51343ENSG00000105325UniProt: Q9UM11

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]

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 109MIM #620145
AD
82
ClinVar variants
23
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— FZR1
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
23 Pathogenic / Likely Pathogenic· 49 VUS of 82 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.17LOEUF
pLI 1.000
Z-score 4.69
OE 0.04 (0.01–0.17)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
3.64Z-score
OE missense 0.43 (0.38–0.50)
143 obs / 328.8 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.04 (0.01–0.17)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.43 (0.38–0.50)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.06
0≤1.21.6
LoF obs/exp: 1 / 27.6Missense obs/exp: 143 / 328.8Syn Z: -0.60

ClinVar Variant Classifications

82 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic21
Likely Pathogenic2
VUS49
Likely Benign6
Benign3
Conflicting1
21
Pathogenic
2
Likely Pathogenic
49
VUS
6
Likely Benign
3
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
4
17
0
21
Likely Pathogenic
0
1
1
0
2
VUS
1
36
10
2
49
Likely Benign
0
2
1
3
6
Benign
0
0
0
3
3
Conflicting
—1
Total14329882

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

FZR1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

FZR1-related intellectual disability and epilepsy

strong
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Developmental and epileptic encephalopathy 109

MIM #620145

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance.
Zhang J et al.·Nature
2018
N 6-methyladenosine Modification of FZR1 mRNA Promotes Gemcitabine Resistance in Pancreatic Cancer.
Su J et al.·Cancer Res
2023
FZR1 loss increases sensitivity to DNA damage and consequently promotes murine and human B-cell acute leukemia.
Ishizawa J et al.·Blood
2017
De novo FZR1 loss-of-function variants cause developmental and epileptic encephalopathies.
Manivannan SN et al.·Brain
2022
The APC/C E3 Ligase Complex Activator FZR1 Restricts BRAF Oncogenic Function.
Wan L et al.·Cancer Discov
2017
FZR1 as a novel biomarker for breast cancer neoadjuvant chemotherapy prediction.
Liu S et al.·Cell Death Dis
2020
Comprehensive Genomic Analysis of Cemento-Ossifying Fibroma.
Gomez RS et al.·Mod Pathol
2024
CYLD deficiency enhances metabolic reprogramming and tumor progression in nasopharyngeal carcinoma via PFKFB3.
Wang L et al.·Cancer Lett
2022
Increased Expression and Prognostic Significance of BYSL in Melanoma.
Wang ZZ et al.·J Immunother
2024
RNA methyltransferase NSUN2 promotes growth of hepatocellular carcinoma cells by regulating fizzy-related-1 in vitro and in vivo.
Zhai CT et al.·Kaohsiung J Med Sci
2021
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools