CYFIP2
protein-codingcytoplasmic FMR1 interacting protein 2, the group of SCAR/WAVE complex
Gene summary
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 cytosol; perinuclear region of cytoplasm; and synapse. Part of SCAR complex. Implicated in developmental and epileptic encephalopathy 65. [provided by Alliance of Genome Resources, Jun 2026]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~129.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0100038
Submitter: ClinGen
*CYFIP2* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2018 (Nakashima et al., PMID: 29534297). The phenotypes of CYFIP2-related complex neurodevelopmental disorder vary from developmental epileptic encephalopathy with severe epilepsy, profound intellectual disability and hypotonia to mild or moderate intellectual disability without seizures. Twenty heterozygous missense variants reported in twenty-eight probands in three publications are included in this curation (PMID: 29534297, 30664714, 33149277). Variants found in most individuals with CYFIP2-related complex neurodevelopmental disorder are of de novo origin. Of the 28 probands, 13 carried hotspot variants at arginine 87 and had developmental epileptic encephalopathy phenotypes. Functional studies of several missense variants including the recurrent p.Arg87Cys variant showed gain-of-function effects (PMID: 29534297, 32486060). While four cases of putative loss-of-function variants have been reported, the Epilepsy GCEP decided not to include these cases in the curation because the role of loss-of-function variants as a disease mechanism is unclear at this time. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. In summary, there is definitive evidence supporting the relationship between *CYFIP2* and autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification has been approved by ClinGen Epilepsy GCEP on the meeting date, May 6, 2025 (SOP version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0033374
Submitter: Illumina
Inheritance Pattern: AD
Disease ID:MONDO:0018614
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0033374
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0033374
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CYFIP2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001037333.3. 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 | 4 | 302 | 10 | 316 | ||
| missense | 5 | 21 | 369 | 76 | 3 | 474 |
| nonsense | 16 | 2 | 18 | |||
| start loss | 0 | |||||
| frameshift | 1 | 10 | 2 | 1 | 14 | |
| splice donor/acceptor (+/-2bp) | 1 | 1 | 15 | 2 | 19 | |
| Total | 6 | 23 | 414 | 384 | 14 | 841 |
Highest pathogenic variant AF is 0.0000065690074
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001032410.1 | 30 | MANE Select | |
| Ensembl | ENSP00000479968.1 | 30 | MANE Select | |
| RefSeq | NP_001278650.1 | 29 | Standard | |
| RefSeq | NP_001278651.1 | 31 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| cyfip2 | Danio rerio | Structure: retinal ganglion cell Quality: mislocalised abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- RNA transport - Homo sapiens (human)
- Regulation of actin cytoskeleton - Homo sapiens (human)
- Regulation of Actin Cytoskeleton
- Signal Transduction
- VEGFA-VEGFR2 Pathway
Biological Process
- cell morphogenesis
- apoptotic process
- axon guidance
- cell projection assembly
- Fc-gamma receptor signaling pathway involved in phagocytosis
Molecular Function
- RNA 7-methylguanosine cap binding
- protein binding
Cellular Component
- nucleus
- cytoplasm
- cytosol
- membrane
- cell junction
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000521420
- Coding exons
- 29
- Length
- 129518
- Individuals with no LoFs
- 125632
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 3
- Defined
- 125635
- p
- 0.0000119
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 6.01 | 274 | 732 | 0.374 | 0.0000442 | 8113 |
| Missense (PolyPhen) | 52 | 197.5 | 0.26329 | 2197 | ||
| Synonymous | -0.160 | 292 | 289 | 1.01 | 0.0000185 | 2272 |
| Loss of Function | 7.43 | 2 | 68.2 | 0.0293 | 0.00000369 | 770 |
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) | 0.000018 | 0.000018 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Involved in T-cell adhesion and p53/TP53-dependent induction of apoptosis. Does not bind RNA. As component of the WAVE1 complex, required for BDNF-NTRK2 endocytic trafficking and signaling from early endosomes (By similarity). {ECO:0000250|UniProtKB:Q5SQX6, ECO:0000269|PubMed:10449408, ECO:0000269|PubMed:15048733, ECO:0000269|PubMed:17245118}.;
- Disease
- DISEASE: Epileptic encephalopathy, early infantile, 65 (EIEE65) [MIM:618008]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. EIEE65 is an autosomal dominant form characterized by onset of intractable seizures usually in the first 6 months of life and severe to profound psychomotor developmental delay. {ECO:0000269|PubMed:29534297}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.505
Essentials
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.827
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |