CYFIP2

Summary

CYFIP2 (cytoplasmic FMR1 interacting protein 2, HGNC:13760) is a protein-coding gene on chromosome 5q33.3, encoding Cytoplasmic FMR1-interacting protein 2 (Q96F07). Involved in T-cell adhesion and p53/TP53-dependent induction of apoptosis.

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.

Source: NCBI Gene 26999 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 15
• Clinical variants (ClinVar): 1,144 total — 6 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 58
• Druggable target: yes
• MANE Select transcript: NM_001037333

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13760
Approved symbol	CYFIP2
Name	cytoplasmic FMR1 interacting protein 2
Location	5q33.3
Locus type	gene with protein product
Status	Approved
Aliases	PIR121
Ensembl gene	ENSG00000055163
Ensembl biotype	protein_coding
OMIM	606323
Entrez	26999

Gene structure

Transcript identifiers

Ensembl transcripts: 53 — 38 protein_coding, 11 retained_intron, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000435847, ENST00000518456, ENST00000518511, ENST00000518555, ENST00000519663, ENST00000520424, ENST00000520942, ENST00000520960, ENST00000521420, ENST00000522463, ENST00000522637, ENST00000522775, ENST00000522884, ENST00000522892, ENST00000523383, ENST00000524058, ENST00000611075, ENST00000611925, ENST00000616178, ENST00000617629, ENST00000618329, ENST00000620254, ENST00000621516, ENST00000622696, ENST00000698888, ENST00000883373, ENST00000883374, ENST00000883375, ENST00000883376, ENST00000883377, ENST00000883378, ENST00000883379, ENST00000883380, ENST00000883381, ENST00000883382, ENST00000883383, ENST00000883384, ENST00000883385, ENST00000883386, ENST00000883387, ENST00000883388, ENST00000883389, ENST00000883390, ENST00000883391, ENST00000922821, ENST00000922822, ENST00000922823, ENST00000922824, ENST00000954621, ENST00000954622, ENST00000954623, ENST00000954624, ENST00000954625

RefSeq mRNA: 4 — MANE Select: NM_001037333 NM_001037333, NM_001291721, NM_001291722, NM_014376

CCDS: CCDS75364, CCDS78077, CCDS78078

Canonical transcript exons

ENST00000620254 — 31 exons

Exon	Start	End
ENSE00002113676	157266123	157266195
ENSE00003469130	157309743	157309834
ENSE00003472682	157307761	157307865
ENSE00003473068	157390521	157390668
ENSE00003473398	157383265	157383359
ENSE00003488726	157339057	157339256
ENSE00003495921	157319762	157319928
ENSE00003500371	157311664	157311781
ENSE00003508515	157382590	157382662
ENSE00003529927	157323921	157324074
ENSE00003530450	157320655	157320802
ENSE00003549879	157326171	157326267
ENSE00003553779	157300715	157300896
ENSE00003561043	157314969	157315094
ENSE00003561360	157314344	157314463
ENSE00003569842	157296673	157296774
ENSE00003588793	157285339	157285478
ENSE00003592534	157360282	157360372
ENSE00003592895	157341070	157341157
ENSE00003611964	157327973	157328049
ENSE00003637069	157330742	157330850
ENSE00003650265	157359005	157359148
ENSE00003662884	157287019	157287108
ENSE00003669250	157389189	157389427
ENSE00003673931	157333327	157333446
ENSE00003675114	157304238	157304366
ENSE00003689580	157361468	157361598
ENSE00003691132	157325482	157325638
ENSE00003736713	157294783	157294860
ENSE00003754402	157392833	157395594
ENSE00003785632	157302794	157302890

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 99.80.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 37.3620 / max 922.2382, expressed in 1602 samples.

FANTOM5 promoters (17 alternative TSS)

Promoter ID	TPM avg	Samples expressed
59798	25.9782	1558
59799	8.1566	941
59801	0.5729	298
59811	0.4441	199
59802	0.4090	244
59817	0.3062	93
59809	0.2932	50
59800	0.2666	106
59820	0.2177	79
59803	0.2163	95

Top tissues by expression

293 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
renal medulla	UBERON:0000362	99.80	gold quality
middle temporal gyrus	UBERON:0002771	99.75	gold quality
saphenous vein	UBERON:0007318	99.70	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.61	gold quality
CA1 field of hippocampus	UBERON:0003881	99.45	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.23	gold quality
entorhinal cortex	UBERON:0002728	99.21	gold quality
primary visual cortex	UBERON:0002436	99.02	gold quality
superior frontal gyrus	UBERON:0002661	98.96	gold quality
parietal lobe	UBERON:0001872	98.91	gold quality
occipital lobe	UBERON:0002021	98.91	gold quality
postcentral gyrus	UBERON:0002581	98.84	gold quality
paraflocculus	UBERON:0005351	98.83	gold quality
frontal pole	UBERON:0002795	98.79	gold quality
orbitofrontal cortex	UBERON:0004167	98.72	gold quality
lateral globus pallidus	UBERON:0002476	98.70	gold quality
substantia nigra pars compacta	UBERON:0001965	98.68	gold quality
Brodmann (1909) area 46	UBERON:0006483	98.68	gold quality
pons	UBERON:0000988	98.63	gold quality
Brodmann (1909) area 10	UBERON:0013541	98.59	gold quality
cerebellar vermis	UBERON:0004720	98.58	gold quality
temporal lobe	UBERON:0001871	98.56	gold quality
middle frontal gyrus	UBERON:0002702	98.53	gold quality
frontal cortex	UBERON:0001870	98.44	gold quality
prefrontal cortex	UBERON:0000451	98.39	gold quality
cerebral cortex	UBERON:0000956	98.37	gold quality
right frontal lobe	UBERON:0002810	98.37	gold quality
Ammon’s horn	UBERON:0001954	98.36	gold quality
neocortex	UBERON:0001950	98.34	gold quality
substantia nigra pars reticulata	UBERON:0001966	98.34	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	46.40
E-ANND-3	yes	14.25
E-MTAB-9067	yes	13.85
E-MTAB-6678	yes	10.27
E-MTAB-7303	no	2474.16
E-GEOD-150728	no	676.88

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXD3, TP53

Literature-anchored findings (GeneRIF, showing 16)

• The CYFIP2 promoter contains a p53-responsive element that confers p53 binding as well as transcriptional activation of a heterologous reporter. (PMID:17245118)
• Protein complexes containing CYFIP/Sra/PIR121 coordinate Arf1 and Rac1 signalling during clathrin-AP-1-coated carrier biogenesis at the trans-golgi network. (PMID:20228810)
• Studies identify a novel proapoptotic gene target, CYFIP2, which is downregulated by IMP-1, and mediates the regulation of cell survival and K-Ras expression in colon cancer cells. (PMID:21252116)
• Increased expression of the cytoplasmic FMR1-interacting protein 2 (CYFIP2), a known FMRP interactor, is detected in fragile X syndrome. (PMID:22268788)
• blood samples of lateral sclerosis patients were found to have significantly different levels of expression of CyFIP2 and RbBP9 compared to the levels of expression in control subjects. (PMID:22430187)
• Study characterized the functional roles of the two brain-specific phosphorylation sites (S582 and T1067) of CYFIP2 in cultured hippocampal neurons; found that overexpression of the phospho-blocking T1067A mutant significantly decreased the density of stubby spines, but not other types of spines. Study found that T1067 phosphorylation of CYFIP2 could potentially weaken the interaction between CYFIP2 and Nap1. (PMID:28692454)
• This study identified de novo CYFIP2 variants at the Arg87 residue in cause early-onset epileptic encephalopathy. (PMID:29534297)
• The current study provides further supports for contribution of CYFIP1/2 in the pathogenesis of autism spectrum disorder (ASD) and potentiates it as a peripheral marker for ASD diagnosis. (PMID:29752658)
• The importance of the ATRX/DAXX pathway was confirmed by the first-ever pancreatic neuroendocrine neoplasms (pNEN)-specific protein-damaging hotspot mutation in DAXX. In this study, both novel genes, including the pro-apoptotic CYFIP2 gene and hedgehog signaling PTCH2, and novel pathways, such as the MAPK-ERK pathway, were implicated in pNEN. (PMID:30021865)
• This study evidenced a variety of de novo variants in CYFIP2 as a novel cause of mostly severe intellectual disability with seizures and muscular hypotonia. (PMID:30664714)
• New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics. (PMID:33149277)
• Cytoplasmic FMR1 interacting protein (CYFIP) family members and their function in neural development and disorders. (PMID:34327661)
• NUAK2 silencing inhibits the proliferation, migration and epithelialtomesenchymal transition of cervical cancer cells via upregulating CYFIP2. (PMID:34558636)
• Molecular Dynamics of CYFIP2 Protein and Its R87C Variant Related to Early Infantile Epileptic Encephalopathy. (PMID:35955843)
• CYFIP2 serves as a prognostic biomarker and correlates with tumor immune microenvironment in human cancers. (PMID:37735711)
• Different dysregulations of CYFIP1 and CYFIP2 in distinct types of dementia. (PMID:38128786)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cyfip2	ENSDARG00000036375
mus_musculus	Cyfip2	ENSMUSG00000020340
rattus_norvegicus	Cyfip2	ENSRNOG00000006557
drosophila_melanogaster	Cyfip	FBGN0038320
caenorhabditis_elegans		WBGENE00001579

Paralogs (1): CYFIP1 (ENSG00000273749)

Protein

Protein identifiers

Cytoplasmic FMR1-interacting protein 2 — Q96F07 (reviewed: Q96F07)

Alternative names: p53-inducible protein 121

All UniProt accessions (11): A0A087WTQ3, A0A087WV63, A0A087WVE1, A0A087WWZ1, A0A087WZL7, A0A8V8TNU3, Q96F07, E5RKA3, E7EVJ5, E7EW33, H7C229

UniProt curated annotations — full annotation on UniProt →

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.

Subunit / interactions. Component of the WAVE1 complex composed of ABI2, CYFIP2, BRK1, NCKAP1 and WASF1/WAVE1. Interacts with FMR1, FXR1 and FXR2. Interacts with FMR1 isoform 6; the interaction occurs in a RNA-dependent manner. Interacts with RAC1 (activated form) which causes the complex to dissociate, releasing activated WASF1. The complex can also be activated by NCK1. Interacts with SHANK3; the interaction mediates the association of SHANK3 with the WAVE1 complex. Interacts with TMEM108 (via N-terminus); the interaction associates TMEM108 with the WAVE1 complex.

Subcellular location. Cytoplasm. Nucleus. Perinuclear region. Synapse. Synaptosome.

Tissue specificity. Expressed in T-cells. Increased expression is observed in CD4(+) T-lymphocytes from patients with multiple sclerosis (at protein level).

Disease relevance. Developmental and epileptic encephalopathy 65 (DEE65) [MIM:618008] A form of epileptic encephalopathy, a heterogeneous group of severe early-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. DEE65 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. The disease is caused by variants affecting the gene represented in this entry.

Induction. By p53/TP53.

Similarity. Belongs to the CYFIP family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96F07-1	1	yes
Q96F07-2	2

RefSeq proteins (4): NP_001032410, NP_001278650, NP_001278651, NP_055191 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008081	Cytoplasmic_FMR1-int	Family
IPR009828	CYRIA/CYRIB_Rac1-bd	Domain

Pfam: PF05994, PF07159

UniProt features (8 total): sequence variant 4, chain 1, modified residue 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96F07-F1	87.28	0.64

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 1062

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-2029482	Regulation of actin dynamics for phagocytic cup formation
R-HSA-4420097	VEGFA-VEGFR2 Pathway
R-HSA-5663213	RHO GTPases Activate WASPs and WAVEs
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-9664422	FCGR3A-mediated phagocytosis

MSigDB gene sets: 445 (showing top): GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_SYNAPSE_ASSEMBLY, GCANCTGNY_MYOD_Q6, GOBP_GROWTH, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, HNF1_Q6, GOMF_GTPASE_BINDING, CTATGCA_MIR153, CHX10_01, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, ATGTTAA_MIR302C

GO Biological Process (12): cell morphogenesis (GO:0000902), apoptotic process (GO:0006915), axon guidance (GO:0007411), cell projection assembly (GO:0030031), regulation of actin filament polymerization (GO:0030833), positive regulation of proteolysis (GO:0045862), positive regulation of neurotrophin TRK receptor signaling pathway (GO:0051388), dendrite extension (GO:0097484), cell-cell adhesion (GO:0098609), regulation of postsynapse assembly (GO:0150052), cell adhesion (GO:0007155), neuron projection development (GO:0031175)

GO Molecular Function (2): small GTPase binding (GO:0031267), protein binding (GO:0005515)

GO Cellular Component (9): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), SCAR complex (GO:0031209), neuron projection (GO:0043005), synapse (GO:0045202), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Fcgamma receptor (FCGR) dependent phagocytosis	1
Signaling by VEGF	1
RHO GTPase Effectors	1
RHO GTPase cycle	1
Leishmania phagocytosis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoplasm	3
anatomical structure morphogenesis	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
axonogenesis	1
neuron projection guidance	1
cellular component assembly	1
cell projection organization	1
regulation of actin polymerization or depolymerization	1
actin filament polymerization	1
regulation of protein polymerization	1
proteolysis	1
regulation of proteolysis	1
positive regulation of protein metabolic process	1
positive regulation of signal transduction	1
neurotrophin TRK receptor signaling pathway	1
regulation of neurotrophin TRK receptor signaling pathway	1
neuron projection extension	1
cell adhesion	1
regulation of synapse assembly	1
postsynapse assembly	1
regulation of postsynapse organization	1
cellular process	1
neuron development	1
plasma membrane bounded cell projection organization	1
GTPase binding	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
protein-containing complex	1
plasma membrane bounded cell projection	1
cell junction	1
extracellular vesicle	1

Protein interactions and networks

STRING

1424 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CYFIP2	ABI2	Q9NYB9	999
CYFIP2	NCKAP1	Q9Y2A7	999
CYFIP2	BRK1	Q8WUW1	999
CYFIP2	ABI1	Q8IZP0	997
CYFIP2	WASF1	Q92558	997
CYFIP2	FXR1	P51114	996
CYFIP2	FXR2	P51116	994
CYFIP2	NCKAP1L	P55160	993
CYFIP2	WASF2	Q9Y6W5	990
CYFIP2	FMR1	Q06787	987
CYFIP2	CRADD	P78560	934
CYFIP2	WAS	P42768	895
CYFIP2	NUFIP2	Q7Z417	835
CYFIP2	WASF3	Q9UPY6	832
CYFIP2	NCK1	P16333	821

IntAct

130 interactions, top by confidence:

A	B	Type	Score
CCDC22	VPS26C	psi-mi:“MI:0914”(association)	0.790
BAIAP2	YWHAQ	psi-mi:“MI:0914”(association)	0.740
PAAT	CLTC	psi-mi:“MI:0914”(association)	0.740
BRK1	HSBP1	psi-mi:“MI:0914”(association)	0.740
NCKAP1	YWHAH	psi-mi:“MI:0914”(association)	0.730
CYFIP2	NCKAP1	psi-mi:“MI:0915”(physical association)	0.650
NCK2	SH3PXD2B	psi-mi:“MI:0914”(association)	0.640
SPG11	AP5Z1	psi-mi:“MI:0914”(association)	0.620
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAB	BLTP3B	psi-mi:“MI:0914”(association)	0.610
ABI3	CYFIP2	psi-mi:“MI:0915”(physical association)	0.560
CYFIP2	ABI1	psi-mi:“MI:0915”(physical association)	0.560
CYFIP2	WASF2	psi-mi:“MI:0915”(physical association)	0.560
ABI1	CYFIP2	psi-mi:“MI:0915”(physical association)	0.560
FMR1	CYFIP2	psi-mi:“MI:0407”(direct interaction)	0.530
FMR1	CYFIP2	psi-mi:“MI:0915”(physical association)	0.530
SYNGAP1	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
NCK1	SH3PXD2B	psi-mi:“MI:0914”(association)	0.530
CBLC	GAK	psi-mi:“MI:0914”(association)	0.530
AMZ1	SUSD5	psi-mi:“MI:0914”(association)	0.530
HSPB9	USP12	psi-mi:“MI:0914”(association)	0.530
WASF3	HOXB9	psi-mi:“MI:0914”(association)	0.530
EPS8L1	DHPS	psi-mi:“MI:0914”(association)	0.530
ILVBL	SLC33A1	psi-mi:“MI:0914”(association)	0.530
NHSL3	NCK2	psi-mi:“MI:0914”(association)	0.530
NCKAP1	NHSL1	psi-mi:“MI:0914”(association)	0.530
WASF3	CYFIP1	psi-mi:“MI:0914”(association)	0.530

BioGRID (217): CYFIP2 (Affinity Capture-MS), CYFIP2 (Affinity Capture-MS), CYFIP2 (Affinity Capture-MS), CYFIP2 (Affinity Capture-MS), CYFIP2 (Affinity Capture-MS), CYFIP2 (Affinity Capture-MS), CYFIP2 (Affinity Capture-MS), CYFIP2 (Affinity Capture-MS), CYFIP2 (Co-fractionation), CYFIP2 (Co-fractionation), CYFIP2 (Co-fractionation), WASF1 (Co-fractionation), WASF2 (Co-fractionation), WASF3 (Co-fractionation), CYFIP2 (Affinity Capture-MS)

ESM2 similar proteins: A1CGW7, A1CXW3, A1Z7L1, A7RU46, B0S6R1, F1QJX5, F1QN74, F6WXT2, O44518, P28660, P55160, P55161, P55162, P55163, Q0CL68, Q16X15, Q23658, Q24134, Q299G2, Q2UG94, Q4WNQ6, Q54IR8, Q54R74, Q5R414, Q5S2C3, Q5SQX6, Q5U430, Q5XHG1, Q60PC0, Q640K3, Q6GQD1, Q6PFJ7, Q6PI53, Q6UK63, Q6ZBH9, Q7L576, Q7Q6D9, Q7TMB8, Q869Q3, Q8IQV9

Diamond homologs: O44518, Q299G2, Q5R414, Q5SQX6, Q6GQD1, Q6UK63, Q7L576, Q7TMB8, Q90YM8, Q96F07, Q9VF87, Q5S2C3

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 162 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
RHO GTPases Activate WASPs and WAVEs	13	38.5×	3e-15
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	5	31.4×	1e-05
Parasite infection	9	29.1×	1e-09
Leishmania phagocytosis	9	29.1×	1e-09
FCGR3A-mediated phagocytosis	14	24.5×	8e-14
Regulation of actin dynamics for phagocytic cup formation	14	24.1×	8e-14
Fcgamma receptor (FCGR) dependent phagocytosis	9	23.4×	9e-09
Signaling by VEGF	9	18.5×	8e-08

GO biological processes:

GO term	Partners	Fold	FDR
actin polymerization or depolymerization	5	26.6×	2e-04
Rac protein signal transduction	6	23.4×	8e-05
lamellipodium assembly	7	21.6×	2e-05
positive regulation of lamellipodium assembly	5	20.9×	6e-04
actin filament polymerization	5	16.7×	1e-03
positive regulation of actin filament polymerization	6	13.8×	7e-04
ephrin receptor signaling pathway	5	11.9×	5e-03
neuron projection morphogenesis	6	11.5×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1144 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	13
Uncertain significance	423
Likely benign	563
Benign	65

Top pathogenic / likely-pathogenic (19)

Variant ID	HGVS	Classification
973747	NM_001037333.3(CYFIP2):c.3594+1G>T	Pathogenic
973748	NM_001037333.3(CYFIP2):c.2099A>G (p.Gln700Arg)	Pathogenic
973749	NM_001037333.3(CYFIP2):c.1917C>G (p.Ile639Met)	Pathogenic
973750	NM_001037333.3(CYFIP2):c.1918G>A (p.Glu640Lys)	Pathogenic
973751	NM_001037333.3(CYFIP2):c.1363G>C (p.Ala455Pro)	Pathogenic
973752	NM_001037333.3(CYFIP2):c.2095G>C (p.Asp699His)	Pathogenic
1065625	NM_001037333.3(CYFIP2):c.2089T>C (p.Cys697Arg)	Likely pathogenic
1995740	NM_001037333.3(CYFIP2):c.344T>C (p.Leu115Pro)	Likely pathogenic
2062031	NM_001037333.3(CYFIP2):c.1915A>T (p.Ile639Phe)	Likely pathogenic
2500808	NM_001037333.3(CYFIP2):c.1651G>C (p.Val551Leu)	Likely pathogenic
2626976	NM_001037333.3(CYFIP2):c.887A>T (p.Asp296Val)	Likely pathogenic
2759831	NM_001037333.3(CYFIP2):c.2108A>G (p.Tyr703Cys)	Likely pathogenic
4813221	NM_001037333.3(CYFIP2):c.2156+2T>G	Likely pathogenic
545427	NM_001037333.3(CYFIP2):c.260G>T (p.Arg87Leu)	Likely pathogenic
802171	NM_001037333.3(CYFIP2):c.259C>A (p.Arg87Ser)	Likely pathogenic
827782	NM_001037333.3(CYFIP2):c.2095G>T (p.Asp699Tyr)	Likely pathogenic
827810	NM_001037333.3(CYFIP2):c.2096A>G (p.Asp699Gly)	Likely pathogenic
973753	NM_001037333.3(CYFIP2):c.322T>C (p.Tyr108His)	Likely pathogenic
987225	NM_001037333.3(CYFIP2):c.2066A>G (p.Glu689Gly)	Likely pathogenic

SpliceAI

5314 predictions. Top by Δscore:

Variant	Effect	Δscore
5:157285333:CTTCA:C	acceptor_loss	1.0000
5:157285334:TTCA:T	acceptor_loss	1.0000
5:157285335:TCA:T	acceptor_loss	1.0000
5:157285336:CA:C	acceptor_loss	1.0000
5:157285337:A:AG	acceptor_gain	1.0000
5:157285337:A:C	acceptor_loss	1.0000
5:157285338:G:GC	acceptor_gain	1.0000
5:157285338:G:T	acceptor_loss	1.0000
5:157285338:GT:G	acceptor_gain	1.0000
5:157285338:GTGC:G	acceptor_gain	1.0000
5:157285338:GTGCA:G	acceptor_gain	1.0000
5:157285475:CCAG:C	donor_gain	1.0000
5:157285476:CAGG:C	donor_loss	1.0000
5:157285477:AGG:A	donor_loss	1.0000
5:157285478:GG:G	donor_loss	1.0000
5:157285479:G:GC	donor_loss	1.0000
5:157294781:A:AG	acceptor_gain	1.0000
5:157294782:G:GG	acceptor_gain	1.0000
5:157296671:AGGT:A	acceptor_gain	1.0000
5:157296672:GGTG:G	acceptor_gain	1.0000
5:157296756:G:GT	donor_gain	1.0000
5:157296774:GGTG:G	donor_loss	1.0000
5:157296775:GTG:G	donor_loss	1.0000
5:157296776:T:A	donor_loss	1.0000
5:157300713:A:AG	acceptor_gain	1.0000
5:157300714:G:GG	acceptor_gain	1.0000
5:157300858:G:GT	donor_gain	1.0000
5:157300892:AAGAG:A	donor_loss	1.0000
5:157300894:G:GT	donor_gain	1.0000
5:157300894:GAG:G	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000000193 (5:157381313 T>C), RS1000003423 (5:157304983 A>C,G), RS1000010991 (5:157322557 G>A), RS1000011808 (5:157391286 G>A,T), RS1000084228 (5:157385366 T>G), RS1000091088 (5:157298947 G>A,T), RS1000116386 (5:157369134 G>A), RS1000131473 (5:157340554 A>C), RS1000145650 (5:157305762 G>A,T), RS1000152485 (5:157322852 T>C,G), RS1000168671 (5:157368905 T>G), RS1000176577 (5:157287240 T>C), RS1000178329 (5:157387321 T>A), RS1000195812 (5:157346758 A>G,T), RS1000259211 (5:157305516 C>G,T)

Disease associations

OMIM: gene MIM:606323 | disease phenotypes: MIM:618008, MIM:209850

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental and epileptic encephalopathy, 65	Definitive	Autosomal dominant
undetermined early-onset epileptic encephalopathy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD

Mondo (5): developmental and epileptic encephalopathy, 65 (MONDO:0033374), complex neurodevelopmental disorder (MONDO:0100038), autism (MONDO:0005260), intellectual disability (MONDO:0001071), undetermined early-onset epileptic encephalopathy (MONDO:0018614)

Orphanet (2): Non-specific syndromic intellectual disability (Orphanet:528084), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

58 total (30 of 58 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000252	Microcephaly
HP:0000348	High forehead
HP:0000494	Downslanted palpebral fissures
HP:0000504	Abnormality of vision
HP:0000508	Ptosis
HP:0000546	Retinal degeneration
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000668	Hypodontia
HP:0000708	Atypical behavior
HP:0000717	Autism
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001268	Mental deterioration
HP:0001272	Cerebellar atrophy
HP:0001273	Abnormal corpus callosum morphology
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001298	Encephalopathy
HP:0001315	Reduced tendon reflexes
HP:0001336	Myoclonus
HP:0001337	Tremor
HP:0001344	Absent speech
HP:0001347	Hyperreflexia

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST003518_6	Daytime sleep phenotypes	7.000000e-06
GCST004185_2	Lung function (FEV1/FVC)	5.000000e-13
GCST006019_28	Gamma glutamyl transferase levels	2.000000e-14
GCST007430_108	Peak expiratory flow	2.000000e-16
GCST007431_102	Lung function (FEV1/FVC)	8.000000e-38
GCST007432_167	FEV1	1.000000e-12
GCST009798_48	Asthma	2.000000e-10
GCST010042_66	Asthma	4.000000e-11
GCST010043_131	Asthma	2.000000e-12
GCST010500_6	T-Cell Immunoglobulin and Mucin domain 1 levels	5.000000e-08
GCST011349_3	Gamma glutamyl transferase levels	4.000000e-14
GCST90011898_128	Alanine aminotransferase levels	5.000000e-15
GCST90013405_60	Liver enzyme levels (alanine transaminase)	6.000000e-15
GCST90013407_64	Liver enzyme levels (gamma-glutamyl transferase)	5.000000e-32
GCST90014325_24	Asthma	8.000000e-10

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007828	daytime rest measurement
EFO:0004713	FEV/FVC ratio
EFO:0004532	serum gamma-glutamyl transferase measurement
EFO:0009718	peak expiratory flow
EFO:0004314	forced expiratory volume
EFO:0010812	T-cell immunoglobulin and mucin domain 1 measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066298 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.21	Kd	6158	nM	CHEMBL3752910
5.16	ED50	6950	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149850: Binding affinity to human CYFIP2 incubated for 45 mins by Kinobead based pull down assay	kd	6.1584	uM

CTD chemical–gene interactions

60 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, increases methylation	6
Aflatoxin B1	affects expression, increases expression, increases methylation	5
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression	4
Fluorouracil	affects reaction, increases reaction, affects response to substance, increases expression	4
Cyclosporine	decreases expression, increases expression	4
Cisplatin	increases expression, affects cotreatment, decreases expression	3
Tretinoin	affects cotreatment, increases expression	3
trichostatin A	affects cotreatment, decreases expression	2
sodium arsenite	decreases expression	2
cupric chloride	decreases expression	2
Estradiol	affects cotreatment, decreases expression	2
Nickel	increases expression	2
Progesterone	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
alpha phellandrene	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
pirinixic acid	increases activity, affects binding, decreases expression	1
bisphenol A	decreases methylation	1
lead acetate	decreases expression	1
sodium arsenate	decreases expression, increases abundance	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
benzo(e)pyrene	affects methylation	1
potassium chromate(VI)	increases expression	1
aflatoxin B2	decreases methylation	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	decreases phosphorylation, decreases reaction, increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652892	Binding	Binding affinity to human CYFIP2 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

1 cell lines: 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C6NH	iPSC R87C C8	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT00036231	PHASE3	TERMINATED	Synthetic Human Secretin in Children With Autism and Gastrointestinal Dysfunction
NCT00036244	PHASE3	COMPLETED	Synthetic Human Secretin in Children With Autism
NCT00065884	PHASE3	UNKNOWN	Valproate Response in Aggressive Autistic Adolescents
NCT00065962	PHASE3	COMPLETED	Secretin for the Treatment of Autism
NCT00252603	PHASE3	COMPLETED	Galantamine Versus Placebo in Childhood Autism
NCT00346736	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00352248	PHASE3	COMPLETED	Randomized Controlled Trial of Acupuncture Versus Sham Acupuncture in Autistic Spectrum Disorder
NCT00352352	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00355329	PHASE3	COMPLETED	Randomized Control Trial of Using Tongue Acupuncture in Autistic Spectrum Disorder Using PET Scan for Clinical Correlation
NCT00498173	PHASE3	COMPLETED	Effectiveness of Atomoxetine in Treating ADHD Symptoms in Children and Adolescents With Autism
NCT00541346	PHASE3	COMPLETED	A Pilot Study of Daytrana TM in Children With Autism Co-Morbid for Attention Deficit Hyperactivity Disorder (ADHD) Symptoms