CYFIP2

Chr 5

cytoplasmic FMR1 interacting protein 2

Also known as: DEE65, EIEE65, PIR121

NCBI Gene: 26999ENSG00000055163UniProt: Q96F07

Predicted to enable small GTPase binding activity. Involved in several processes, including cell-cell adhesion; positive regulation of proteolysis; and regulation of postsynapse assembly. Located in perinuclear region of cytoplasm and synapse. Part of SCAR complex. Implicated in developmental and epileptic encephalopathy 65. [provided by Alliance of Genome Resources, Jul 2025]

Primary Disease Associations & Inheritance

UniProtDevelopmental and epileptic encephalopathy 65
689
ClinVar variants
9
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— CYFIP2
🧬
Gene-Disease Validity (ClinGen)
complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
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
9 Pathogenic / Likely Pathogenic· 235 VUS of 689 total submissions
Some data sources returned errors (2)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

omim: Error: OMIM fetch failed: 429

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.
0.09LOEUF
pLI 1.000
Z-score 7.43
OE 0.03 (0.01–0.09)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

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.
6.01Z-score
OE missense 0.37 (0.34–0.41)
274 obs / 731.7 exp
Constrained

Extremely missense-constrained (top ~0.01%)

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.0.03 (0.01–0.09)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.37 (0.34–0.41)
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.1.01
0≤1.21.6
LoF obs/exp: 2 / 68.2Missense obs/exp: 274 / 731.7Syn Z: -0.16

ClinVar Variant Classifications

689 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4
Likely Pathogenic5
VUS235
Likely Benign388
Benign42
Conflicting15
4
Pathogenic
5
Likely Pathogenic
235
VUS
388
Likely Benign
42
Benign
15
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
4
0
4
Likely Pathogenic
0
4
1
0
5
VUS
11
198
25
1
235
Likely Benign
2
34
164
188
388
Benign
0
2
25
15
42
Conflicting
—15
Total13238219204689

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

View in ClinVar →

Protein Context — Lollipop Plot

CYFIP2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

CYFIP2-related epileptic encephalopathy, early infantile

definitive
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Recent advances in CYFIP2-associated neurodevelopmental disorders: From human genetics to molecular mechanisms and mouse models.
Ma R et al.·Brain Dev
2025Review
Molecular Dynamics of CYFIP2 Protein and Its R87C Variant Related to Early Infantile Epileptic Encephalopathy.
Biembengut ÍV et al.·Int J Mol Sci
2022
A novel variant in CYFIP2 in a girl with severe disabilities and bilateral perisylvian polymicrogyria.
Salokivi T et al.·Am J Med Genet A
2024Case report
Functional impact of CYFIP2 RNA editing on actin regulation, axon growth, and spinogenesis.
La Via L et al.·Neurochem Int
2025Functional
De novo hotspot variants in CYFIP2 cause early-onset epileptic encephalopathy.
Nakashima M et al.·Ann Neurol
2018
CYFIP2 serves as a prognostic biomarker and correlates with tumor immune microenvironment in human cancers.
Peng Q et al.·Eur J Med Res
2023
ELK3-CYFIP2 axis-mediated actin remodeling modulates metastasis and natural killer cell responses in triple-negative breast cancer.
Choi SH et al.·J Exp Clin Cancer Res
2025Functional
New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics.
Begemann A et al.·Genet Med
2021
Fragile X-like behaviors and abnormal cortical dendritic spines in cytoplasmic FMR1-interacting protein 2-mutant mice.
Han K et al.·Hum Mol Genet
2015
Genetic variants modulate gene expression statin response in human lymphoblastoid cell lines.
Theusch E et al.·BMC Genomics
2020Meta-analysis
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