CYFIP2

Chr 5AD

cytoplasmic FMR1 interacting protein 2

Also known as: DEE65, EIEE65, PIR121

NCBI Gene: 26999 ENSG00000055163 UniProt: Q96F07 OMIM: 606323

CYFIP2 encodes a protein that binds small GTPases and regulates synapse assembly as part of the SCAR complex. Autosomal dominant loss-of-function mutations cause developmental and epileptic encephalopathy 65. The gene is highly intolerant to loss-of-function variants, indicating haploinsufficiency as the mechanism of pathogenicity.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.091 OMIM phenotype

Clinical Summary— CYFIP2

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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ClinVar Variants

22 unique Pathogenic / Likely Pathogenic· 438 VUS of 1174 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.03 (0.01–0.09)

0≤0.351.4

Missense OE?0.37 (0.34–0.41)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 2 / 68.2Missense obs/exp: 274 / 731.7Syn Z: -0.16

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveCYFIP2-related epileptic encephalopathy, early infantileOTHERAD

This gene — mechanism propensity

0.2997th %ile

GOF

0.4875th %ile

LOF

0.73top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · LOEUF 0.09

GOF1 literature citation · 91% of P/LP are missense

Literature Evidence

GOFOur findings suggest that de novo Arg87 variants in CYFIP2 have gain-of-function effects on the WAVE signaling pathway and are associated with severe neurological disorders.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 29534297 ↗

ClinVar Variant Classifications

1174 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic16

VUS438

Likely Benign589

Benign66

Conflicting33

Pathogenic

Likely Pathogenic

438

VUS

589

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	5	0	0	6
Likely Pathogenic	1	15	0	0	16
VUS	30	377	29	2	438
Likely Benign	6	57	240	286	589
Benign	1	3	37	25	66
Conflicting	—				33
Total	39	457	306	313	1,148

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

View in ClinVar →

16 pathogenic / likely-pathogenic (of 25) ClinVar copy-number / structural variants overlap CYFIP2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →