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 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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 65MIM #618008

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · complex neurodevelopmental disorder · AD · ClinGen 2025

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.09

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in CYFIP2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 130

953 rare PASS variants

Rare truncating (LoF)

1 in 5,500

57 rare PASS variants

Rare synonymous (reference)

1 in 51

630 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CYFIP2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 180	1 in 7,900
South Asian	~43k	1 in 140	1 in 4,100
Remaining (unassigned)	~30k	1 in 130	1 in 3,200
European (Finnish)	~27k	1 in 250	1 in 2,700
Admixed American	~22k	1 in 140	1 in 2,800
African / African American	~21k	1 in 130	1 in 3,200
East Asian	~20k	1 in 110	1 in 2,700
Ashkenazi Jewish	~13k	1 in 580	≈ 1 in 6,000
Middle Eastern	~2,884	1 in 120	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.