NCKAP1

Summary

NCKAP1 (NCK associated protein 1, HGNC:7666) is a protein-coding gene on chromosome 2q32.1, encoding Nck-associated protein 1 (Q9Y2A7). Part of the WAVE complex that regulates lamellipodia formation. It is a selective cancer dependency (DepMap: 47.2% of cell lines) and haploinsufficient (ClinGen: sufficient evidence).

Contributes to small GTPase binding activity. Involved in Rac protein signal transduction; positive regulation of Arp2/3 complex-mediated actin nucleation; and positive regulation of lamellipodium assembly. Located in extracellular exosome and focal adhesion. Part of SCAR complex.

Source: NCBI Gene 10787 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 230 total — 10 pathogenic, 13 likely-pathogenic
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 47.2% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_013436

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7666
Approved symbol	NCKAP1
Name	NCK associated protein 1
Location	2q32.1
Locus type	gene with protein product
Status	Approved
Aliases	Nap1, HEM2, NAP125
Ensembl gene	ENSG00000061676
Ensembl biotype	protein_coding
OMIM	604891
Entrez	10787

Gene structure

Transcript identifiers

Ensembl transcripts: 31 — 25 protein_coding, 4 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000360982, ENST00000361354, ENST00000471640, ENST00000477988, ENST00000478449, ENST00000492058, ENST00000493359, ENST00000495619, ENST00000703824, ENST00000703825, ENST00000888536, ENST00000888537, ENST00000888538, ENST00000888539, ENST00000888540, ENST00000888541, ENST00000939370, ENST00000939371, ENST00000939372, ENST00000939373, ENST00000966159, ENST00000966160, ENST00000966161, ENST00000966162, ENST00000966163, ENST00000966164, ENST00000966165, ENST00000966166, ENST00000966167, ENST00000966168, ENST00000966169

RefSeq mRNA: 2 — MANE Select: NM_013436 NM_013436, NM_205842

CCDS: CCDS2287, CCDS2288

Canonical transcript exons

ENST00000361354 — 31 exons

Exon	Start	End
ENSE00001156475	182952405	182952502
ENSE00001156483	182952793	182952923
ENSE00001156489	182953113	182953331
ENSE00001223390	182928117	182928226
ENSE00001823640	183037992	183038457
ENSE00002204829	182995701	182995838
ENSE00002204891	182964676	182964808
ENSE00002209880	183002974	183003030
ENSE00002230595	182982821	182982927
ENSE00002234320	182994839	182994887
ENSE00002236619	183001953	183002043
ENSE00002259361	182967216	182967361
ENSE00002263671	183003233	183003325
ENSE00002268689	183002127	183002269
ENSE00002271512	182956462	182956593
ENSE00002276559	183023806	183023916
ENSE00002280676	182981244	182981376
ENSE00002284889	182986171	182986227
ENSE00002285193	182978834	182978915
ENSE00002296717	182926816	182926905
ENSE00002297444	182983286	182983382
ENSE00002307875	182989030	182989186
ENSE00002312011	182976893	182976951
ENSE00002314004	182957457	182957596
ENSE00003610215	182935293	182935375
ENSE00003657037	182942070	182942163
ENSE00003661466	182930695	182930788
ENSE00003676216	182962159	182962278
ENSE00003682466	182934752	182934832
ENSE00003691887	182928783	182928899
ENSE00003711222	182909115	182925818

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 98.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 33.6690 / max 216.4703, expressed in 1665 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
32771	21.7690	1633
32770	11.9001	1599

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
seminal vesicle	UBERON:0000998	98.84	gold quality
frontal pole	UBERON:0002795	98.66	gold quality
upper arm skin	UBERON:0004263	98.66	gold quality
choroid plexus epithelium	UBERON:0003911	98.61	gold quality
cerebellar vermis	UBERON:0004720	98.45	gold quality
ganglionic eminence	UBERON:0004023	98.41	gold quality
ventricular zone	UBERON:0003053	98.40	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.39	gold quality
cortical plate	UBERON:0005343	98.34	gold quality
oral cavity	UBERON:0000167	98.32	gold quality
orbitofrontal cortex	UBERON:0004167	98.32	gold quality
pharyngeal mucosa	UBERON:0000355	98.28	gold quality
mammary duct	UBERON:0001765	98.28	gold quality
mucosa of paranasal sinus	UBERON:0005030	98.28	gold quality
jejunal mucosa	UBERON:0000399	98.22	gold quality
calcaneal tendon	UBERON:0003701	98.18	gold quality
penis	UBERON:0000989	98.14	gold quality
substantia nigra pars reticulata	UBERON:0001966	98.13	gold quality
jejunum	UBERON:0002115	98.09	gold quality
substantia nigra pars compacta	UBERON:0001965	98.06	gold quality
mammalian vulva	UBERON:0000997	98.05	gold quality
islet of Langerhans	UBERON:0000006	98.04	gold quality
lateral globus pallidus	UBERON:0002476	98.03	gold quality
urethra	UBERON:0000057	98.02	gold quality
dorsal root ganglion	UBERON:0000044	98.01	gold quality
skin of hip	UBERON:0001554	97.99	gold quality
cardia of stomach	UBERON:0001162	97.96	gold quality
tongue squamous epithelium	UBERON:0006919	97.95	silver quality
superior vestibular nucleus	UBERON:0007227	97.90	gold quality
popliteal artery	UBERON:0002250	97.89	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	12.08
E-MTAB-6379	no	74.38

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ZBTB4

miRNA regulators (miRDB)

118 targeting NCKAP1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4282	99.99	75.36	6408
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 47.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 8)

• we show that stapled peptides targeting the interface between NCKAP1 and CYFIP1 destabilize the WASF3 complex… thereby suppressing invasion and metastasis of breast cancer cells. (PMID:27432794)
• We identify three mosaic missense and likely-gene disrupting mutations in genes previously implicated in ASD (KMT2C, NCKAP1, and MYH10) in probands but none in siblings. We find a strong ascertainment bias for mosaic mutations in probands relative to their unaffected siblings (PMID:27632392)
• miR-34c-3p functions as a tumor promoter by targeting NCKAP1 that is associated with prognosis in hepatocellular carcinoma. (PMID:27704267)
• Results demonstrate the importance and functional regulation of the HSP90-NAP1 protein complex in cancer metastatic signaling. (PMID:30867003)
• NCKAP1 is a tumor suppress gene that modulates the cell cycle of HCC cell lines by targeting Rb1/p53 regulation. (PMID:31068575)
• NCKAP1 Disruptive Variants Lead to a Neurodevelopmental Disorder with Core Features of Autism. (PMID:33157009)
• Circ_NCKAP1 promotes skin basal cell carcinoma progression by sponging the miR-148b-5p/HSP90 axis. (PMID:34533810)
• Role of NCKAP1 in the Defective Phagocytic Function of Microglia-Like Cells Derived from Rapidly Progressing Sporadic ALS. (PMID:37154887)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	nckap1	ENSDARG00000060853
mus_musculus	Nckap1	ENSMUSG00000027002
rattus_norvegicus	Nckap1	ENSRNOG00000007518
drosophila_melanogaster	Hem	FBGN0011771
caenorhabditis_elegans		WBGENE00001580

Paralogs (1): NCKAP1L (ENSG00000123338)

Protein

Protein identifiers

Nck-associated protein 1 — Q9Y2A7 (reviewed: Q9Y2A7)

Alternative names: Membrane-associated protein HEM-2, p125Nap1

All UniProt accessions (3): Q9Y2A7, A0A994J4I5, A0A994J6K9

UniProt curated annotations — full annotation on UniProt →

Function. Part of the WAVE complex that regulates lamellipodia formation. The WAVE complex regulates actin filament reorganization via its interaction with the Arp2/3 complex. Actin remodeling activity is regulated by RAC1. 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, CYFIP1 or CYFIP2, BRK1, NCKAP1 and WASF1/WAVE1. Within the complex, a heterodimer containing NCKAP1 and CYFIP1 interacts with a heterotrimer formed by WAVE1, ABI2 and BRK1. Component of the WAVE2 complex composed of ABI1, CYFIP1/SRA1, NCKAP1/NAP1 and WASF2/WAVE2. CYFIP2 binds to activated RAC1 which causes the complex to dissociate, releasing activated WASF1. The complex can also be activated by NCK1. Associates preferentially with the first SH3 domain of NCK. Interacts with NYAP1, NYAP2 and MYO16. Interacts with TMEM132D. (Microbial infection) Interacts with human cytomegalovirus protein UL135.

Subcellular location. Cell membrane. Cell projection. Lamellipodium membrane.

Tissue specificity. Expressed in all tissues examined except peripheral blood leukocytes, with highest expression in brain, heart, and skeletal muscle. Expressed in cells of various brain regions including Purkinje cells and dentate nucleus of the cerebellum, CA4 region and dentate gyrus of the hippocampus, and in frontal gray and white matter.

Similarity. Belongs to the HEM-1/HEM-2 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y2A7-1	1	yes
Q9Y2A7-2	2

RefSeq proteins (2): NP_038464, NP_995314 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019137	Nck-associated_protein-1	Family

Pfam: PF09735

UniProt features (101 total): helix 69, strand 13, turn 11, initiator methionine 1, chain 1, transmembrane region 1, region of interest 1, compositionally biased region 1, modified residue 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
3P8C	X-RAY DIFFRACTION	2.29
4N78	X-RAY DIFFRACTION	2.43
7USC	ELECTRON MICROSCOPY	3
7USD	ELECTRON MICROSCOPY	3
7USE	ELECTRON MICROSCOPY	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y2A7-F1	92.75	0.82

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): 2

Function

Pathways and Gene Ontology

Reactome pathways

23 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-9013404	RAC2 GTPase cycle
R-HSA-9013423	RAC3 GTPase cycle
R-HSA-9664422	FCGR3A-mediated phagocytosis
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-194138	Signaling by VEGF
R-HSA-194315	Signaling by Rho GTPases
R-HSA-195258	RHO GTPase Effectors
R-HSA-2029480	Fcgamma receptor (FCGR) dependent phagocytosis
R-HSA-5663205	Infectious disease
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases
R-HSA-9012999	RHO GTPase cycle
R-HSA-9658195	Leishmania infection
R-HSA-9664407	Parasite infection
R-HSA-9664417	Leishmania phagocytosis
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3
R-HSA-9824443	Parasitic Infection Pathways

MSigDB gene sets: 352 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_UP, GOBP_APICAL_PROTEIN_LOCALIZATION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_BODY_MORPHOGENESIS, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_AXIS_SPECIFICATION, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_EMBRYONIC_AXIS_SPECIFICATION, GOBP_REGULATION_OF_ACTIN_NUCLEATION, AMIT_EGF_RESPONSE_60_HELA, GOLDRATH_IMMUNE_MEMORY, GOBP_NEUROGENESIS

GO Biological Process (31): cell morphogenesis (GO:0000902), in utero embryonic development (GO:0001701), somitogenesis (GO:0001756), neural tube closure (GO:0001843), apoptotic process (GO:0006915), zygotic determination of anterior/posterior axis, embryo (GO:0007354), central nervous system development (GO:0007417), endoderm development (GO:0007492), mesodermal cell migration (GO:0008078), embryonic body morphogenesis (GO:0010172), positive regulation of lamellipodium assembly (GO:0010592), cell migration (GO:0016477), Rac protein signal transduction (GO:0016601), cell projection assembly (GO:0030031), lamellipodium assembly (GO:0030032), positive regulation of actin filament polymerization (GO:0030838), cortical actin cytoskeleton organization (GO:0030866), establishment or maintenance of actin cytoskeleton polarity (GO:0030950), regulation of protein localization (GO:0032880), embryonic heart tube development (GO:0035050), cell migration involved in gastrulation (GO:0042074), basal protein localization (GO:0045175), apical protein localization (GO:0045176), paraxial mesoderm morphogenesis (GO:0048340), notochord morphogenesis (GO:0048570), embryonic foregut morphogenesis (GO:0048617), neuron projection morphogenesis (GO:0048812), protein stabilization (GO:0050821), positive regulation of Arp2/3 complex-mediated actin nucleation (GO:2000601), notochord development (GO:0030903), paraxial mesoderm development (GO:0048339)

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

GO Cellular Component (12): ruffle (GO:0001726), cytosol (GO:0005829), focal adhesion (GO:0005925), lamellipodium (GO:0030027), SCAR complex (GO:0031209), lamellipodium membrane (GO:0031258), filamentous actin (GO:0031941), extracellular exosome (GO:0070062), postsynapse (GO:0098794), plasma membrane (GO:0005886), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
RHO GTPase cycle	3
Signaling by Rho GTPases	2
Fcgamma receptor (FCGR) dependent phagocytosis	1
Signaling by VEGF	1
RHO GTPase Effectors	1
Leishmania phagocytosis	1
Immune System	1
Signaling by Receptor Tyrosine Kinases	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Innate Immune System	1
Disease	1
Signal Transduction	1
Parasitic Infection Pathways	1
Leishmania infection	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
chordate embryonic development	2
actin cytoskeleton organization	2
cell leading edge	2
plasma membrane bounded cell projection	2
cytoplasm	2
protein-containing complex	2
anatomical structure morphogenesis	1
anterior/posterior pattern specification	1
segmentation	1
anatomical structure formation involved in morphogenesis	1
somite development	1
primary neural tube formation	1
tube closure	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
anterior/posterior axis specification, embryo	1
nervous system development	1
system development	1
tissue development	1
ameboidal-type cell migration	1
body morphogenesis	1
embryonic morphogenesis	1
regulation of lamellipodium assembly	1
lamellipodium assembly	1
positive regulation of plasma membrane bounded cell projection assembly	1
positive regulation of lamellipodium organization	1
cell motility	1
small GTPase-mediated signal transduction	1
cellular component assembly	1
cell projection organization	1
lamellipodium organization	1
plasma membrane bounded cell projection assembly	1
actin filament polymerization	1
regulation of actin filament polymerization	1
positive regulation of protein polymerization	1
positive regulation of cytoskeleton organization	1
positive regulation of supramolecular fiber organization	1
cortical cytoskeleton organization	1

Protein interactions and networks

STRING

1602 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NCKAP1	BRK1	Q8WUW1	999
NCKAP1	CYFIP2	Q96F07	999
NCKAP1	ABI2	Q9NYB9	998
NCKAP1	CYFIP1	Q7L576	998
NCKAP1	ABI1	Q8IZP0	998
NCKAP1	WASF1	Q92558	998
NCKAP1	WASF2	Q9Y6W5	990
NCKAP1	WASF3	Q9UPY6	968
NCKAP1	ABI3	Q9P2A4	944
NCKAP1	NCK1	P16333	924
NCKAP1	WAS	P42768	850
NCKAP1	RAC1	P15154	691
NCKAP1	WASL	O00401	658
NCKAP1	ACTR2	P61160	640
NCKAP1	GRM1	Q13255	630

IntAct

191 interactions, top by confidence:

A	B	Type	Score
NCKAP1	ABI1	psi-mi:“MI:0915”(physical association)	0.910
ABI1	NCKAP1	psi-mi:“MI:0915”(physical association)	0.910
ABI1	NCKAP1	psi-mi:“MI:0407”(direct interaction)	0.910
NCKAP1	CYFIP1	psi-mi:“MI:0915”(physical association)	0.900
CYFIP1	NCKAP1	psi-mi:“MI:0407”(direct interaction)	0.900
CYFIP1	NCKAP1	psi-mi:“MI:0915”(physical association)	0.900
ABI2	CYFIP1	psi-mi:“MI:0915”(physical association)	0.870
SGF29	NDC80	psi-mi:“MI:0914”(association)	0.840
NCKAP1	YWHAB	psi-mi:“MI:0915”(physical association)	0.760
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
VASP	CEP43	psi-mi:“MI:0914”(association)	0.740

BioGRID (304): NCKAP1 (Affinity Capture-MS), NCKAP1 (Affinity Capture-MS), NCKAP1 (Affinity Capture-MS), NCKAP1 (Affinity Capture-MS), NCKAP1 (Affinity Capture-MS), NCKAP1 (Affinity Capture-MS), NCKAP1 (Affinity Capture-MS), CYFIP1 (Co-fractionation), CYFIP2 (Co-fractionation), ETF1 (Co-fractionation), NCKAP1 (Co-fractionation), NCKAP1 (Co-fractionation), WASF1 (Co-fractionation), WASF2 (Co-fractionation), NCKAP1 (Affinity Capture-MS)

ESM2 similar proteins: A4IH75, B0S6R1, F4K265, O14417, O75165, O94915, P28660, P60670, P97878, Q10LJ0, Q2HJE0, Q2TBN7, Q3B736, Q3B8G8, Q3TPX4, Q499N2, Q4R6Q7, Q4R708, Q556Y9, Q5E9X5, Q5R6U8, Q5R8B7, Q5RBT3, Q5VZE5, Q5XHA1, Q5ZHV2, Q642Q3, Q6AY69, Q6DE58, Q6DKG0, Q6GLR7, Q6NPF4, Q6P2C8, Q6PFL0, Q6PHQ8, Q6Q7J5, Q7T322, Q8BJ63, Q8TAT6, Q8VDP2

Diamond homologs: A7RU46, B0S6R1, P28660, P55160, P55161, P55162, P55163, Q640K3, Q8K1X4, Q9Y2A7

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
NCKAP1	“form complex”	“WRC complex”	binding
NCKAP1	“up-regulates activity”	NHS	binding
NCKAP1	“form complex”	“WAVE complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 172 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	16	43.4×	3e-20
Activation of BAD and translocation to mitochondria	5	32.5×	1e-05
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	5	28.7×	2e-05
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	5	28.7×	2e-05
FCGR3A-mediated phagocytosis	17	27.2×	6e-18
Regulation of actin dynamics for phagocytic cup formation	17	26.8×	6e-18
Parasite infection	9	26.6×	3e-09
Leishmania phagocytosis	9	26.6×	3e-09

GO biological processes:

GO term	Partners	Fold	FDR
Rac protein signal transduction	7	25.2×	6e-06
actin polymerization or depolymerization	5	24.6×	4e-04
positive regulation of lamellipodium assembly	5	19.3×	1e-03
clathrin-dependent endocytosis	5	18.6×	1e-03
lamellipodium assembly	6	17.1×	4e-04
positive regulation of actin filament polymerization	7	14.8×	2e-04
cell motility	5	12.9×	3e-03
protein targeting	5	11.7×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	13
Uncertain significance	150
Likely benign	15
Benign	6

Top pathogenic / likely-pathogenic (23)

Variant ID	HGVS	Classification
1878674	NM_013436.5(NCKAP1):c.2113C>T (p.Arg705Ter)	Pathogenic
2637936	NM_013436.5(NCKAP1):c.1861C>T (p.Gln621Ter)	Pathogenic
3343859	NM_013436.5(NCKAP1):c.2392C>T (p.Arg798Ter)	Pathogenic
3377027	NM_013436.5(NCKAP1):c.1488T>G (p.Tyr496Ter)	Pathogenic
3390619	NM_013436.5(NCKAP1):c.2749C>T (p.Arg917Ter)	Pathogenic
3773720	NM_013436.5(NCKAP1):c.2111del (p.Pro704fs)	Pathogenic
3917872	NM_013436.5(NCKAP1):c.883_886del (p.Leu295fs)	Pathogenic
4056304	NM_013436.5(NCKAP1):c.1004+1G>A	Pathogenic
4281358	NM_013436.5(NCKAP1):c.3118_3127del (p.Ala1040fs)	Pathogenic
834055	NM_013436.5(NCKAP1):c.3240_3241del (p.Asn1080fs)	Pathogenic
1174105	NM_013436.5(NCKAP1):c.2191C>T (p.Gln731Ter)	Likely pathogenic
1302561	NM_013436.5(NCKAP1):c.2226T>G (p.Ser742Arg)	Likely pathogenic
1696649	NM_013436.5(NCKAP1):c.684_687del (p.Gln228fs)	Likely pathogenic
1708234	NM_013436.5(NCKAP1):c.155del (p.Asn52fs)	Likely pathogenic
2530332	NM_013436.5(NCKAP1):c.3165_3176del (p.Lys1056_Leu1059del)	Likely pathogenic
3064095	NM_013436.5(NCKAP1):c.3280G>T (p.Glu1094Ter)	Likely pathogenic
3376855	NM_013436.5(NCKAP1):c.2007G>T (p.Arg669Ser)	Likely pathogenic
3771977	NM_013436.5(NCKAP1):c.790+1G>A	Likely pathogenic
3893334	NM_013436.5(NCKAP1):c.922G>A (p.Glu308Lys)	Likely pathogenic
3910199	NM_013436.5(NCKAP1):c.634del (p.Met212fs)	Likely pathogenic
4293564	NM_013436.5(NCKAP1):c.885_886del (p.Phe296fs)	Likely pathogenic
4820137	NM_013436.5(NCKAP1):c.1263dup (p.Tyr422fs)	Likely pathogenic
977624	NM_013436.5(NCKAP1):c.778A>T (p.Lys260Ter)	Likely pathogenic

SpliceAI

4574 predictions. Top by Δscore:

Variant	Effect	Δscore
2:182925682:T:C	donor_gain	1.0000
2:182925815:CAAT:C	acceptor_gain	1.0000
2:182926902:CAAG:C	acceptor_gain	1.0000
2:182926907:T:C	acceptor_gain	1.0000
2:182926907:T:TC	acceptor_gain	1.0000
2:182926915:A:C	acceptor_gain	1.0000
2:182926919:A:C	acceptor_gain	1.0000
2:182928111:ACAT:A	donor_loss	1.0000
2:182928112:CAT:C	donor_loss	1.0000
2:182928113:AT:A	donor_loss	1.0000
2:182928114:TAC:T	donor_loss	1.0000
2:182928115:A:AC	donor_gain	1.0000
2:182928115:A:T	donor_loss	1.0000
2:182928115:ACCG:A	donor_gain	1.0000
2:182928116:C:CC	donor_gain	1.0000
2:182928116:CCG:C	donor_gain	1.0000
2:182928116:CCGC:C	donor_gain	1.0000
2:182928777:TATTA:T	donor_loss	1.0000
2:182928778:ATTAC:A	donor_loss	1.0000
2:182928779:TTAC:T	donor_loss	1.0000
2:182928780:TAC:T	donor_loss	1.0000
2:182928782:CCTT:C	donor_gain	1.0000
2:182928895:GTTTT:G	acceptor_gain	1.0000
2:182928896:TTTT:T	acceptor_gain	1.0000
2:182928897:TTT:T	acceptor_gain	1.0000
2:182928898:TT:T	acceptor_gain	1.0000
2:182928898:TTCTA:T	acceptor_loss	1.0000
2:182928899:TCTA:T	acceptor_loss	1.0000
2:182928900:C:CC	acceptor_gain	1.0000
2:182935291:A:AC	donor_gain	1.0000

AlphaMissense

7486 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:182925746:C:G	A1115P	1.000
2:182925750:T:A	R1113S	1.000
2:182925750:T:G	R1113S	1.000
2:182925751:C:A	R1113I	1.000
2:182925751:C:G	R1113T	1.000
2:182925757:A:C	L1111W	1.000
2:182925757:A:G	L1111S	1.000
2:182925766:G:A	P1108L	1.000
2:182925766:G:C	P1108R	1.000
2:182925766:G:T	P1108H	1.000
2:182925767:G:A	P1108S	1.000
2:182925767:G:T	P1108T	1.000
2:182925769:A:G	F1107S	1.000
2:182925771:A:C	C1106W	1.000
2:182925772:C:T	C1106Y	1.000
2:182925773:A:G	C1106R	1.000
2:182925778:T:A	E1104V	1.000
2:182925779:C:T	E1104K	1.000
2:182925781:A:G	L1103S	1.000
2:182925784:A:G	L1102P	1.000
2:182925787:T:A	D1101V	1.000
2:182925796:A:C	L1098R	1.000
2:182925796:A:G	L1098P	1.000
2:182925796:A:T	L1098H	1.000
2:182926823:A:G	L1088P	1.000
2:182926826:A:G	L1087P	1.000
2:182926886:A:G	L1067P	1.000
2:182926886:A:T	L1067Q	1.000
2:182926889:A:G	L1066P	1.000
2:182926898:G:A	S1063F	1.000

dbSNP variants (sampled 300 via entrez): RS1000044371 (2:183029061 G>A), RS1000044501 (2:183039980 C>A,T), RS1000070091 (2:183007757 G>C), RS1000105240 (2:182911049 G>A), RS1000106673 (2:182998024 A>G), RS1000140230 (2:183012972 C>T), RS1000145014 (2:182940370 G>A), RS1000151678 (2:182920905 A>C), RS1000156539 (2:182955736 A>T), RS1000259844 (2:182941855 G>T), RS1000268316 (2:182971702 C>T), RS1000279164 (2:183004646 G>A), RS1000279707 (2:182961117 CTT>C), RS1000295615 (2:182918006 C>T), RS1000302171 (2:182978630 T>C)

Disease associations

OMIM: gene MIM:604891 | disease phenotypes: MIM:618982

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Strong	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): autism spectrum disorder (MONDO:0005258), neurodevelopmental disorder (MONDO:0700092), intellectual disability (MONDO:0001071), complex neurodevelopmental disorder (MONDO:0100038), immunodeficiency 72 with autoinflammation (MONDO:0033551)

Orphanet (3): Non-specific syndromic intellectual disability (Orphanet:528084), NON RARE IN EUROPE: Autism (Orphanet:106), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST008478_7	Neurological blood protein biomarker levels	2.000000e-10

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067155 (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
5.81	Kd	1546	nM	CHEMBL5653589
5.81	ED50	1546	nM	CHEMBL5653589

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-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148832: Binding affinity to human NCKAP1 incubated for 45 mins by Kinobead based pull down assay	kd	1.5459	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cadmium	increases palmitoylation, increases expression, decreases reaction, increases abundance	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Valproic Acid	affects expression, decreases methylation	2
Cadmium Chloride	decreases reaction, increases abundance, increases palmitoylation, increases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression, affects localization	1
arsenite	affects binding, decreases reaction	1
methylparaben	increases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	increases expression	1
butyraldehyde	decreases expression	1
2-bromopalmitate	increases abundance, increases palmitoylation, decreases reaction	1
perfluorooctanoic acid	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
perfluoro-n-nonanoic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
perfluorohexanesulfonic acid	increases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
jinfukang	decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Bortezomib	increases expression	1
Temozolomide	decreases expression	1
Sunitinib	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
CHEMBL5651874	Binding	Binding affinity to human NCKAP1 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

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TA06	HAP1 NCKAP1 (-) 1	Cancer cell line	Male
CVCL_TA07	HAP1 NCKAP1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in 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
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
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
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder