NCKAP1L

Summary

NCKAP1L (NCK associated protein 1 like, HGNC:4862) is a protein-coding gene on chromosome 12q13.13-q13.2, encoding Nck-associated protein 1-like (P55160). Essential hematopoietic-specific regulator of the actin cytoskeleton.

This gene encodes a member of the HEM family of tissue-specific transmembrane proteins which are highly conserved from invertebrates through mammals. This gene is only expressed in hematopoietic cells. The encoded protein is a part of the Scar/WAVE complex which plays an important role in regulating cell shape in both metazoans and plants. Alternatively spliced transcript variants encoding different isoforms have been found.

Source: NCBI Gene 3071 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency 72 with autoinflammation (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 569 total — 3 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 14
• Druggable target: yes
• MANE Select transcript: NM_005337

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4862
Approved symbol	NCKAP1L
Name	NCK associated protein 1 like
Location	12q13.13-q13.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000123338
Ensembl biotype	protein_coding
OMIM	141180
Entrez	3071

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 5 protein_coding, 4 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000293373, ENST00000545638, ENST00000547500, ENST00000548221, ENST00000548916, ENST00000548980, ENST00000549451, ENST00000552211, ENST00000858318, ENST00000858319, ENST00000858320

RefSeq mRNA: 2 — MANE Select: NM_005337 NM_001184976, NM_005337

CCDS: CCDS31813, CCDS53799

Canonical transcript exons

ENST00000293373 — 31 exons

Exon	Start	End
ENSE00000939333	54497752	54497891
ENSE00000939335	54500533	54500625
ENSE00000939336	54507853	54507909
ENSE00000939337	54508389	54508531
ENSE00000939338	54509669	54509759
ENSE00000939339	54509848	54509985
ENSE00000939345	54517533	54517642
ENSE00000939346	54517806	54517938
ENSE00000939347	54518651	54518732
ENSE00002353232	54542575	54548243
ENSE00003472830	54523825	54523956
ENSE00003473546	54518914	54518972
ENSE00003475420	54531743	54531825
ENSE00003485584	54521119	54521238
ENSE00003492417	54511803	54511851
ENSE00003515577	54536944	54537053
ENSE00003539704	54531491	54531584
ENSE00003548039	54499355	54499465
ENSE00003570651	54516239	54516295
ENSE00003584901	54520694	54520826
ENSE00003588117	54528247	54528377
ENSE00003593842	54523394	54523539
ENSE00003597751	54538884	54538973
ENSE00003603636	54526528	54526746
ENSE00003603813	54532170	54532250
ENSE00003612375	54531260	54531357
ENSE00003616998	54535104	54535197
ENSE00003618818	54516896	54516992
ENSE00003671981	54519187	54519332
ENSE00003675023	54536129	54536245
ENSE00003682954	54511949	54512105

Expression profiles

Bgee: expression breadth ubiquitous, 242 present calls, max score 97.49.

FANTOM5 (CAGE): breadth broad, TPM avg 41.2540 / max 485.8784, expressed in 643 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
125921	34.6213	635
125920	6.5108	568
125922	0.1219	62

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	97.49	gold quality
leukocyte	CL:0000738	97.34	gold quality
mononuclear cell	CL:0000842	97.33	gold quality
granulocyte	CL:0000094	96.51	gold quality
blood	UBERON:0000178	95.62	gold quality
lymph node	UBERON:0000029	95.56	gold quality
bone marrow cell	CL:0002092	95.51	gold quality
vermiform appendix	UBERON:0001154	94.80	gold quality
spleen	UBERON:0002106	94.47	gold quality
olfactory bulb	UBERON:0002264	94.24	silver quality
type B pancreatic cell	CL:0000169	94.03	gold quality
bone marrow	UBERON:0002371	93.88	gold quality
caecum	UBERON:0001153	93.34	gold quality
trabecular bone tissue	UBERON:0002483	92.69	gold quality
thymus	UBERON:0002370	91.22	gold quality
buccal mucosa cell	CL:0002336	90.57	silver quality
cervix squamous epithelium	UBERON:0006922	90.30	gold quality
muscle layer of sigmoid colon	UBERON:0035805	88.96	gold quality
diaphragm	UBERON:0001103	88.52	gold quality
rectum	UBERON:0001052	87.69	gold quality
tongue squamous epithelium	UBERON:0006919	87.69	gold quality
superficial temporal artery	UBERON:0001614	87.62	gold quality
vena cava	UBERON:0004087	87.59	silver quality
upper lobe of left lung	UBERON:0008952	87.54	gold quality
right lung	UBERON:0002167	87.34	gold quality
small intestine Peyer’s patch	UBERON:0003454	87.12	gold quality
upper lobe of lung	UBERON:0008948	87.07	gold quality
tonsil	UBERON:0002372	86.75	gold quality
triceps brachii	UBERON:0001509	86.72	silver quality
tibial artery	UBERON:0007610	86.69	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	17.07
E-CURD-88	yes	4.35
E-MTAB-5061	no	3.80

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

33 targeting NCKAP1L, 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-MIR-335-3P	99.93	73.36	4958
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-4517	99.76	69.19	1867
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-3682-3P	99.58	67.63	865
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-889-3P	99.40	69.76	2103
HSA-MIR-1272	99.34	68.79	878
HSA-MIR-4528	99.18	69.77	1936
HSA-MIR-6809-5P	99.13	68.45	1223
HSA-MIR-6894-5P	98.70	63.78	809
HSA-MIR-6796-3P	98.68	65.49	689
HSA-MIR-224-5P	98.33	70.12	1256
HSA-MIR-1233-5P	98.19	66.71	1201
HSA-MIR-6778-5P	98.19	66.59	1239
HSA-MIR-1322	97.98	68.96	625
HSA-MIR-5088-5P	97.97	64.28	487
HSA-MIR-3159	97.94	66.79	1098
HSA-MIR-493-3P	97.50	66.44	731
HSA-MIR-194-3P	97.36	65.96	1027
HSA-MIR-214-5P	97.34	66.50	617
HSA-MIR-4662A-3P	97.02	67.77	941
HSA-MIR-874-5P	96.93	63.92	1014
HSA-MIR-99A-3P	92.55	62.10	99
HSA-MIR-99B-3P	92.55	62.30	99

Literature-anchored findings (GeneRIF, showing 8)

• versatile Hem-1-containing complexes coordinate diverse regulatory signals at the leading edge of polarized neutrophils, including but not confined to those involving Verprolin-homologous protein-dependent actin polymerization (PMID:16417406)
• the Hem-1/Nap1 component of the Scar/WAVE complex localizes to propagating waves that appear to organize the leading edge of a motile neutrophil (PMID:17696648)
• the evolutionarily conserved HEM1 protein simultaneously regulates filamentous actin (F-actin) and mTORC2 signaling to achieve equipoise in immune responses. (PMID:32647003)
• Prognostic Value of DNA Methylation-Driven Genes in Clear Cell Renal Cell Carcinoma: A Study Based on Methylation and Transcriptome Analyses. (PMID:32733620)
• NCKAP1L defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation. (PMID:32766723)
• Long non-coding RNA PVT1/microRNA miR-3127-5p/NCK-associated protein 1-like axis participates in the pathogenesis of abdominal aortic aneurysm by regulating vascular smooth muscle cells. (PMID:34898354)
• HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions. (PMID:35869404)
• Potential predictive value of immune-related genes FUCA1 and NCKAP1L for osteosarcoma metastasis. (PMID:38844271)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	nckap1l	ENSDARG00000075748
mus_musculus	Nckap1l	ENSMUSG00000022488
rattus_norvegicus	Nckap1l	ENSRNOG00000036829
drosophila_melanogaster	Hem	FBGN0011771
caenorhabditis_elegans		WBGENE00001580

Paralogs (1): NCKAP1 (ENSG00000061676)

Protein

Protein identifiers

Nck-associated protein 1-like — P55160 (reviewed: P55160)

Alternative names: Hematopoietic protein 1, Membrane-associated protein HEM-1

All UniProt accessions (2): F8W050, P55160

UniProt curated annotations — full annotation on UniProt →

Function. Essential hematopoietic-specific regulator of the actin cytoskeleton. Controls lymphocyte development, activation, proliferation and homeostasis, erythrocyte membrane stability, as well as phagocytosis and migration by neutrophils and macrophages. Component of the WAVE2 complex which signals downstream of RAC to stimulate F-actin polymerization. Required for stabilization and/or translation of the WAVE2 complex proteins in hematopoietic cells. Within the WAVE2 complex, enables the cortical actin network to restrain excessive degranulation and granule release by T-cells. Required for efficient T-lymphocyte and neutrophil migration. Exhibits complex cycles of activation and inhibition to generate waves of propagating the assembly with actin. Also involved in mechanisms WAVE-independent to regulate myosin and actin polymerization during neutrophil chemotaxis. In T-cells, required for proper mechanistic target of rapamycin complex 2 (mTORC2)-dependent AKT phosphorylation, cell proliferation and cytokine secretion, including that of IL2 and TNF.

Subunit / interactions. In hematopoietic cells, component of the WAVE2 complex composed of ABI1, CYFIP1/SRA1, NCKAP1L/HEM1 and WASF2/WAVE2. Interacts with ARHGAP4, PIK3C3/VPS34 and PPP1R12A/MYPT1. Interacts with mammalian target of rapamycin complex 2 (mTORC2) components, including MTOR and RICTOR.

Subcellular location. Cell membrane. Cytoplasm.

Tissue specificity. Expressed only in cells of hematopoietic origin. Expressed in neutrophils (at protein level). Expressed in T-cells (at protein level).

Disease relevance. Immunodeficiency 72 with autoinflammation and lymphoproliferation (IMD72) [MIM:618982] An autosomal recessive immunologic disorder characterized by onset in the first year of life, recurrent bacterial and viral skin infections, severe respiratory tract infections leading to pneumonia and bronchiectasis, and poor specific antibody responses. Patients also exhibit atopic and inflammatory disease alongside chronic hepatosplenomegaly, lymphoproliferation and lymphadenopathy, and autoimmune manifestations. The disease is caused by variants affecting the gene represented in this entry.

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

Isoforms (2)

UniProt ID	Names	Canonical?
P55160-1	1	yes
P55160-2	2

RefSeq proteins (2): NP_001171905, NP_005328* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019137	Nck-associated_protein-1	Family

Pfam: PF09735

UniProt features (15 total): sequence variant 6, sequence conflict 3, compositionally biased region 2, chain 1, transmembrane region 1, region of interest 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P55160-F1	92.83	0.82

Function

Pathways and Gene Ontology

Reactome pathways

24 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-6798695	Neutrophil degranulation
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: 510 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, WALLACE_PROSTATE_CANCER_RACE_UP, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_NEGATIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_B_CELL_HOMEOSTASIS, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_POSITIVE_REGULATION_OF_ERYTHROCYTE_DIFFERENTIATION, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_MYELOID_LEUKOCYTE_MIGRATION

GO Biological Process (36): cell morphogenesis (GO:0000902), B cell homeostasis (GO:0001782), myeloid cell homeostasis (GO:0002262), positive regulation of leukocyte migration (GO:0002687), chemotaxis (GO:0006935), response to xenobiotic stimulus (GO:0009410), cell migration (GO:0016477), maintenance of cell polarity (GO:0030011), cell projection assembly (GO:0030031), positive regulation of actin filament polymerization (GO:0030838), cortical actin cytoskeleton organization (GO:0030866), positive regulation of B cell proliferation (GO:0030890), negative regulation of interleukin-17 production (GO:0032700), negative regulation of interleukin-6 production (GO:0032715), positive regulation of cell adhesion mediated by integrin (GO:0033630), erythrocyte homeostasis (GO:0034101), intracellular signal transduction (GO:0035556), positive regulation of T cell proliferation (GO:0042102), T cell homeostasis (GO:0043029), negative regulation of apoptotic process (GO:0043066), negative regulation of cytotoxic T cell degranulation (GO:0043318), positive regulation of CD4-positive, alpha-beta T cell differentiation (GO:0043372), positive regulation of CD8-positive, alpha-beta T cell differentiation (GO:0043378), positive regulation of B cell differentiation (GO:0045579), positive regulation of gamma-delta T cell differentiation (GO:0045588), positive regulation of lymphocyte differentiation (GO:0045621), positive regulation of erythrocyte differentiation (GO:0045648), neuron projection morphogenesis (GO:0048812), erythrocyte development (GO:0048821), B cell receptor signaling pathway (GO:0050853), positive regulation of phagocytosis, engulfment (GO:0060100), protein-containing complex assembly (GO:0065003), actin polymerization-dependent cell motility (GO:0070358), positive regulation of neutrophil chemotaxis (GO:0090023), positive regulation of neutrophil migration (GO:1902624), positive regulation of TORC2 signaling (GO:1904515)

GO Molecular Function (5): GTPase activator activity (GO:0005096), protein kinase activator activity (GO:0030295), protein-containing complex binding (GO:0044877), TORC2 complex binding (GO:1904841), protein binding (GO:0005515)

GO Cellular Component (8): cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), secretory granule membrane (GO:0030667), SCAR complex (GO:0031209), extracellular exosome (GO:0070062), ficolin-1-rich granule membrane (GO:0101003), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
RHO GTPase cycle	3
Innate Immune System	2
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
Disease	1
Signal Transduction	1
Parasitic Infection Pathways	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
lymphocyte homeostasis	2
response to chemical	2
positive regulation of lymphocyte proliferation	2
negative regulation of cytokine production	2
intracellular anatomical structure	2
binding	2
cytoplasm	2
anatomical structure morphogenesis	1
immune system process	1
homeostasis of number of cells	1
positive regulation of immune system process	1
regulation of leukocyte migration	1
positive regulation of cell migration	1
leukocyte migration	1
taxis	1
cell motility	1
establishment or maintenance of cell polarity	1
cellular component assembly	1
cell projection organization	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
actin cytoskeleton organization	1
cortical cytoskeleton organization	1
regulation of B cell proliferation	1
B cell proliferation	1
positive regulation of B cell activation	1
interleukin-17 production	1
regulation of interleukin-17 production	1
interleukin-6 production	1
regulation of interleukin-6 production	1
cell adhesion mediated by integrin	1
regulation of cell adhesion mediated by integrin	1
positive regulation of cell adhesion	1
myeloid cell homeostasis	1
signal transduction	1
T cell proliferation	1

Protein interactions and networks

STRING

1390 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NCKAP1L	CYFIP1	Q7L576	995
NCKAP1L	BRK1	Q8WUW1	995
NCKAP1L	ABI1	Q8IZP0	994
NCKAP1L	CYFIP2	Q96F07	993
NCKAP1L	WASF2	Q9Y6W5	993
NCKAP1L	WASF1	Q92558	979
NCKAP1L	ABI2	Q9NYB9	975
NCKAP1L	ABI3	Q9P2A4	895
NCKAP1L	WASF3	Q9UPY6	880
NCKAP1L	WAS	P42768	740
NCKAP1L	NCK1	P16333	612
NCKAP1L	GRM1	Q13255	609
NCKAP1L	WIPF1	O43516	601
NCKAP1L	ACTR2	P61160	532
NCKAP1L	WDR1	O75083	523

IntAct

12 interactions, top by confidence:

A	B	Type	Score
BRK1	HSBP1	psi-mi:“MI:0914”(association)	0.740
NCKAP1L	H3-4	psi-mi:“MI:0915”(physical association)	0.400
GAS7	NCKAP1L	psi-mi:“MI:0915”(physical association)	0.400
NOTCH1	CNOT1	psi-mi:“MI:0914”(association)	0.350
ABI2	OBSL1	psi-mi:“MI:0914”(association)	0.350
BRK1	KIF5C	psi-mi:“MI:0914”(association)	0.350
ABI2	NCKAP1L	psi-mi:“MI:0914”(association)	0.350
	ESYT2	psi-mi:“MI:0914”(association)	0.350
LARP7	SBNO1	psi-mi:“MI:2364”(proximity)	0.270
DDX6	RPSA2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (18): ANXA2 (Co-fractionation), CYFIP1 (Co-fractionation), CYFIP2 (Co-fractionation), NCKAP1L (Co-fractionation), NCKAP1L (Affinity Capture-MS), NCKAP1L (Proximity Label-MS), HIST3H3 (Proximity Label-MS), NCKAP1L (Affinity Capture-RNA), NCKAP1L (Affinity Capture-MS), WASF2 (Affinity Capture-Western), NCKAP1L (Affinity Capture-Western), NCKAP1L (Affinity Capture-MS), NCKAP1L (Affinity Capture-MS), NCKAP1L (Cross-Linking-MS (XL-MS)), NCKAP1L (Affinity Capture-RNA)

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

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	7
Uncertain significance	182
Likely benign	320
Benign	29

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
1185045	NM_005337.5(NCKAP1L):c.385C>T (p.Arg129Trp)	Pathogenic
2444019	NM_005337.5(NCKAP1L):c.421G>T (p.Val141Phe)	Pathogenic
2444020	NM_005337.5(NCKAP1L):c.2862+1G>A	Pathogenic
1810260	NM_005337.5(NCKAP1L):c.784+2T>G	Likely pathogenic
2585458	NM_005337.5(NCKAP1L):c.2T>C (p.Met1Thr)	Likely pathogenic
3383987	NM_005337.5(NCKAP1L):c.1111A>C (p.Met371Leu)	Likely pathogenic
4279070	NM_005337.5(NCKAP1L):c.1492G>A (p.Val498Met)	Likely pathogenic
4279071	NM_005337.5(NCKAP1L):c.3346G>A (p.Ala1116Thr)	Likely pathogenic
976847	NM_005337.5(NCKAP1L):c.1555G>C (p.Val519Leu)	Likely pathogenic
976849	NM_005337.5(NCKAP1L):c.773G>T (p.Arg258Leu)	Likely pathogenic

SpliceAI

3997 predictions. Top by Δscore:

Variant	Effect	Δscore
12:54497888:GAAG:G	donor_gain	1.0000
12:54497889:AAG:A	donor_loss	1.0000
12:54497892:GTAA:G	donor_loss	1.0000
12:54499354:GACTT:G	acceptor_gain	1.0000
12:54499461:GCACG:G	donor_gain	1.0000
12:54500531:A:AG	acceptor_gain	1.0000
12:54500532:G:GG	acceptor_gain	1.0000
12:54500532:GC:G	acceptor_gain	1.0000
12:54500532:GCA:G	acceptor_gain	1.0000
12:54500532:GCAA:G	acceptor_gain	1.0000
12:54500532:GCAAC:G	acceptor_gain	1.0000
12:54507910:G:GG	donor_gain	1.0000
12:54508530:GG:G	donor_gain	1.0000
12:54508531:GG:G	donor_gain	1.0000
12:54508537:T:G	donor_gain	1.0000
12:54509667:A:AG	acceptor_gain	1.0000
12:54509667:AGT:A	acceptor_gain	1.0000
12:54509667:AGTG:A	acceptor_loss	1.0000
12:54509668:G:GA	acceptor_gain	1.0000
12:54509668:GT:G	acceptor_gain	1.0000
12:54509668:GTG:G	acceptor_gain	1.0000
12:54509668:GTGA:G	acceptor_gain	1.0000
12:54509668:GTGAC:G	acceptor_gain	1.0000
12:54509986:G:GG	donor_gain	1.0000
12:54511800:CAGA:C	acceptor_loss	1.0000
12:54511801:A:AG	acceptor_gain	1.0000
12:54511801:AGAT:A	acceptor_gain	1.0000
12:54511802:G:GG	acceptor_gain	1.0000
12:54511802:GAT:G	acceptor_gain	1.0000
12:54511802:GATG:G	acceptor_gain	1.0000

AlphaMissense

7459 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:54507869:T:C	L108P	0.999
12:54518958:T:A	W489R	0.999
12:54518958:T:C	W489R	0.999
12:54531320:T:C	L856P	0.999
12:54531353:T:C	L867P	0.999
12:54531778:G:A	G912R	0.999
12:54531778:G:C	G912R	0.999
12:54531778:G:T	G912W	0.999
12:54531779:G:A	G912E	0.999
12:54497833:T:C	L15P	0.998
12:54497854:G:A	G22D	0.998
12:54497872:G:C	R28P	0.998
12:54500624:G:C	R102P	0.998
12:54507872:T:C	L109P	0.998
12:54508420:T:C	L132P	0.998
12:54511842:T:A	W259R	0.998
12:54511842:T:C	W259R	0.998
12:54518968:T:C	L492P	0.998
12:54523508:A:C	S665R	0.998
12:54523510:T:A	S665R	0.998
12:54523510:T:G	S665R	0.998
12:54526581:C:A	P737H	0.998
12:54528267:G:C	R799T	0.998
12:54528268:A:C	R799S	0.998
12:54528268:A:T	R799S	0.998
12:54528275:A:C	S802R	0.998
12:54528277:C:A	S802R	0.998
12:54528277:C:G	S802R	0.998
12:54531296:G:A	G848D	0.998
12:54531763:C:A	R907S	0.998

dbSNP variants (sampled 300 via entrez): RS1000010931 (12:54528929 C>A,G,T), RS1000018234 (12:54541562 C>T), RS1000076906 (12:54522132 G>A), RS1000079146 (12:54548572 T>A,C), RS1000138887 (12:54516086 A>G,T), RS1000205239 (12:54515286 G>A,C), RS1000320770 (12:54515601 G>A), RS1000377152 (12:54528107 G>T), RS1000492767 (12:54502723 A>G), RS1000496091 (12:54500977 A>G), RS1000548134 (12:54508705 A>T), RS1000610839 (12:54501273 G>A), RS1000614612 (12:54540092 G>T), RS1000745811 (12:54514614 C>T), RS1000866303 (12:54507535 C>G,T)

Disease associations

OMIM: gene MIM:141180 | disease phenotypes: MIM:618982

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency 72 with autoinflammation	Strong	Autosomal recessive
immunodeficiency disease	Strong	Autosomal recessive

Mondo (2): immunodeficiency 72 with autoinflammation (MONDO:0033551), immunodeficiency disease (MONDO:0021094)

Orphanet (0):

HPO phenotypes

14 total (14 of 14 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000403	Recurrent otitis media
HP:0001433	Hepatosplenomegaly
HP:0002110	Bronchiectasis
HP:0002716	Lymphadenopathy
HP:0002719	Recurrent infections
HP:0003212	Increased circulating IgE concentration
HP:0003237	Increased circulating IgG concentration
HP:0003593	Infantile onset
HP:0005404	Increased total B cell count
HP:0012302	Herpes simplex encephalitis
HP:0032163	Molluscum contagiosum
HP:0032184	Increased memory T cell proportion
HP:0100759	Clubbing of fingers

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001762_700	Obesity-related traits	3.000000e-06
GCST008156_135	Hip circumference adjusted for BMI	8.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005116	urinary metabolite measurement
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724620 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Nickel	decreases expression, increases expression	2
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
decabromobiphenyl ether	decreases expression	1
sodium arsenite	increases expression	1
tetrabromobisphenol A	decreases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
theaflavin-3,3’-digallate	affects expression	1
Air Pollutants	increases abundance, affects expression	1
Air Pollutants, Occupational	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Ozone	affects expression, increases abundance	1
Testosterone	decreases expression	1
Tretinoin	increases expression	1
Triclosan	increases expression	1
Valproic Acid	affects expression	1
Antirheumatic Agents	decreases expression	1
Okadaic Acid	increases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651875	Binding	Binding affinity to human NCKAP1L 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

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00001542	PHASE4	COMPLETED	Fluconazole Prophylaxis of Thrush in AIDS
NCT00144157	PHASE4	COMPLETED	Open Label Study of NVP+CBV Treatment in Women Who Have Received sdNVP for the pMTCT of HIV
NCT00162643	PHASE4	UNKNOWN	PI Vs. NNRTI Based Therapy for HIV Advanced Disease
NCT00273988	PHASE4	COMPLETED	Pharmacokinetic Study of Interaction Between Nevirapine and Methadone in HIV-1 Infected, Opioid-dependent Adults
NCT00981318	PHASE4	TERMINATED	Pilot Assessment of Lopinavir/Ritonavir and Maraviroc
NCT01086878	PHASE4	COMPLETED	Safety of Cotrimoxazole in HIV- and HAART-exposed Infants
NCT01090102	PHASE4	COMPLETED	Mesalamine to Reduce T Cell Activation in HIV Infection
NCT01147042	PHASE4	TERMINATED	Biochemical Response to Interferon-Gamma in Subjects With Specific Gene Mutation in Chronic Granulomatous Disease
NCT01230580	PHASE4	UNKNOWN	Protease Inhibitor Monotherapy Versus Ongoing Triple-therapy in the Long Term Management of HIV Infection (PIVOT)
NCT01465958	PHASE4	COMPLETED	Pharmacokinetics, Safety, and Tolerability of Subcutaneous GAMUNEX-C in Pediatric Subjects With Primary Immunodeficiency
NCT02274662	PHASE4	COMPLETED	Expanded Access Protocol Thymus Transplantation
NCT02348177	PHASE4	COMPLETED	Pharmacokinetics of Lopinavir/Ritonavir Superboosting in Infants and Young Children Co-infected With HIV and TB
NCT02396979	PHASE4	COMPLETED	Intervention of HIV, Drug Use and the Criminal Justice System in Malaysia
NCT02490956	PHASE4	UNKNOWN	Diagnostic Immunization With Rabies Vaccine in Patients With PID
NCT02503293	PHASE4	COMPLETED	A Study to Compare Quality of Life and Satisfaction in Primary Immunodeficient Patients Treated With Subcutaneous Injections of Gammanorm® 165 mg/mL Administered With Two Different Delivery Devices: Injections Using Pump or Rapid Push
NCT02881437	PHASE4	COMPLETED	IgG Level in Primary Immunodeficiency Switching From Standard SCIG to Every Other Week HyQvia
NCT03033745	PHASE4	COMPLETED	Safety and Tolerability of Higher Infusion Parameters of IgPro20 (Hizentra) in Subjects With Primary Immunodeficiency (PID)
NCT03677557	PHASE4	UNKNOWN	Safety, Tolerability, Patient Satisfaction and Cost of 16.5% Subcutaneous Immunoglobulin (Cutaquig®) Treatment
NCT04192487	PHASE4	COMPLETED	Effects of Crofelemer on the Gut Microbiome in Healthy Volunteers and in HIV+ Patients With Non-Infectious Diarrhea
NCT04566692	PHASE4	COMPLETED	A Study to Evaluate IGSC 20% Biweekly Dosing in Treatment-Experienced Participants and Loading/Maintenance Dosing in Treatment-Naïve Participants With Primary Immunodeficiency
NCT05493969	PHASE4	NOT_YET_RECRUITING	Efficacy and Tolerability of DTG Plus 3TC in HIV Infected Adults With Virologically Suppression and TDF Toxicity
NCT06576024	PHASE4	COMPLETED	Immunogenicity and Safety of Inactivated Hepatitis A Vaccine in HIV-infected People
NCT06634641	PHASE4	RECRUITING	Clozapine-related Immunodeficiency in Parkinsons Disease
NCT07076446	PHASE4	ACTIVE_NOT_RECRUITING	An Open-label, Multicenter Study to Assess the Pharmacokinetics (PK), Safety, and Tolerability of Subcutaneous IgPro20 in Immunoglobulin (IG) Treatment-naïve Participants With Primary Immunodeficiency (PID)
NCT00000118	PHASE3	COMPLETED	Ganciclovir Implant Study for Cytomegalovirus Retinitis
NCT00000134	PHASE3	COMPLETED	Studies of the Ocular Complications of AIDS (SOCA)–Cytomegalovirus Retinitis Retreatment Trial (CRRT)
NCT00000590	PHASE3	COMPLETED	Anti-HIV Immunoglobulin (HIVIG) in Prevention of Maternal-Fetal HIV Transmission (Pediatric ACTG Protocol 185)
NCT00001267	PHASE3	COMPLETED	A Randomized Pilot Study for the Treatment of AIDS or AIDS Related Complex With an Alternating or Simultaneous Combination Regimen of AZT and 2’,3’-Dideoxyinosine
NCT00001646	PHASE3	COMPLETED	Voriconazole vs. Amphotericin B in the Treatment of Invasive Aspergillosis
NCT00144183	PHASE3	COMPLETED	A Study of Single Dose Nevirapine (NVP) Combined With Combivir® for the Prevention of Mother to Child Transmission (pMTCT) - Treatment Options Preservation Study (TOPS)
NCT00243568	PHASE3	WITHDRAWN	Vicriviroc, a CCR5 Inhibitor, Added to an Optimized Antiretroviral Therapy for Previously Treated HIV (VICTOR-E2) (Study P04285
NCT00278954	PHASE3	COMPLETED	Efficacy, Safety and Pharmacokinetics of Gammaplex in Primary Immunodeficiency Diseases.
NCT00474370	PHASE3	COMPLETED	Vicriviroc in HIV-Treatment Experienced Subjects (Study P04889AM8)(COMPLETED)
NCT00478231	PHASE3	COMPLETED	Multicenter, Safety Study Of Maraviroc
NCT00523211	PHASE3	COMPLETED	Vicriviroc in HIV-Treatment Experienced Subjects (Study P04405AM5)
NCT00698334	PHASE3	COMPLETED	Efficacy of Thrice Weekly Directly Observed Treatment, Short-course (DOTS) in HIV-associated Tuberculosis
NCT00966160	PHASE3	COMPLETED	CD4 Cell Recovery in HIV-1 Patients Comparing 2 Treatment Regimes
NCT01363011	PHASE3	COMPLETED	Cobicistat-containing Highly Active Antiretroviral Regimens in HIV-1 Infected Patients With Mild to Moderate Renal Impairment
NCT01440569	PHASE3	COMPLETED	Safety and Efficacy of Cobicistat-boosted Darunavir in HIV Infected Adults
NCT01475838	PHASE3	COMPLETED	Study to Evaluate Switching From Regimens Consisting of a Ritonavir-boosted Protease Inhibitor Plus Emtricitabine/Tenofovir Fixed-Dose Combination to the Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF Single-Tablet Regimen in Virologically Suppressed, HIV-1 Infected Patients