CYFIP2

Chr 5AD

cytoplasmic FMR1 interacting protein 2

Also known as: DEE65, EIEE65, PIR121

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.

OMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
MultiplemechanismADLOEUF 0.091 OMIM phenotype
Clinical SummaryCYFIP2
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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.

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Dual constrained — LoF & missense intolerant
LoF Constraint
0.09LOEUF
pLI 1.000
Z-score 7.43
OE 0.03 (0.010.09)
Highly constrained

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

Missense Constraint
6.01Z-score
OE missense 0.37 (0.340.41)
274 obs / 731.7 exp
Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios
LoF OE0.03 (0.010.09)
00.351.4
Missense OE0.37 (0.340.41)
00.61.4
Synonymous OE1.01
01.21.6
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
DN
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

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.PMID:29534297

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

ClinVar Variant Classifications

0 submitted variants 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.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

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Clinical Literature
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