NOS1AP

Summary

NOS1AP (nitric oxide synthase 1 adaptor protein, HGNC:16859) is a protein-coding gene on chromosome 1q23.3, encoding Carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase protein (O75052). Adapter protein involved in neuronal nitric-oxide (NO) synthesis regulation via its association with nNOS/NOS1.

This gene encodes a cytosolic protein that binds to the signaling molecule, neuronal nitric oxide synthase (nNOS). This protein has a C-terminal PDZ-binding domain that mediates interactions with nNOS and an N-terminal phosphotyrosine binding (PTB) domain that binds to the small monomeric G protein, Dexras1. Studies of the related mouse and rat proteins have shown that this protein functions as an adapter protein linking nNOS to specific targets, such as Dexras1 and the synapsins. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 9722 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nephrotic syndrome, type 22 (Strong, GenCC)
• GWAS associations: 240
• Clinical variants (ClinVar): 122 total — 2 pathogenic
• Phenotypes (HPO): 25
• MANE Select transcript: NM_014697

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16859
Approved symbol	NOS1AP
Name	nitric oxide synthase 1 adaptor protein
Location	1q23.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0464, CAPON
Ensembl gene	ENSG00000198929
Ensembl biotype	protein_coding
OMIM	605551
Entrez	9722

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000361897, ENST00000430120, ENST00000454693, ENST00000464284, ENST00000493151, ENST00000530878, ENST00000870884

RefSeq mRNA: 3 — MANE Select: NM_014697 NM_001126060, NM_001164757, NM_014697

CCDS: CCDS1237, CCDS44267, CCDS53421

Canonical transcript exons

ENST00000361897 — 10 exons

Exon	Start	End
ENSE00000958775	162154405	162154476
ENSE00001042228	162343835	162343976
ENSE00001042234	162300633	162300706
ENSE00001042243	162287344	162287436
ENSE00001042247	162333017	162333125
ENSE00001042255	162355187	162355353
ENSE00001068172	162356960	162357136
ENSE00001445962	162069691	162070282
ENSE00001871384	162367052	162370475
ENSE00003599110	162365404	162365569

Expression profiles

Bgee: expression breadth ubiquitous, 203 present calls, max score 90.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.4261 / max 265.3112, expressed in 1130 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
6289	9.2069	1089
6290	0.9603	386
6291	0.1668	79
6294	0.0920	39

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
CA1 field of hippocampus	UBERON:0003881	90.47	gold quality
type B pancreatic cell	CL:0000169	89.09	gold quality
olfactory bulb	UBERON:0002264	88.78	gold quality
cerebellar vermis	UBERON:0004720	86.84	gold quality
frontal pole	UBERON:0002795	85.95	gold quality
orbitofrontal cortex	UBERON:0004167	85.70	gold quality
cervix squamous epithelium	UBERON:0006922	85.69	gold quality
prefrontal cortex	UBERON:0000451	85.66	gold quality
paraflocculus	UBERON:0005351	85.52	gold quality
cerebellum	UBERON:0002037	85.49	gold quality
cerebellar cortex	UBERON:0002129	85.47	gold quality
cerebellar hemisphere	UBERON:0002245	85.41	gold quality
hair follicle	UBERON:0002073	85.40	gold quality
right hemisphere of cerebellum	UBERON:0014890	85.30	gold quality
frontal cortex	UBERON:0001870	85.23	gold quality
superior frontal gyrus	UBERON:0002661	84.89	gold quality
Brodmann (1909) area 46	UBERON:0006483	84.86	gold quality
parietal lobe	UBERON:0001872	84.82	gold quality
Brodmann (1909) area 9	UBERON:0013540	84.47	gold quality
neocortex	UBERON:0001950	84.42	gold quality
postcentral gyrus	UBERON:0002581	84.20	gold quality
diaphragm	UBERON:0001103	84.18	gold quality
lateral nuclear group of thalamus	UBERON:0002736	84.13	gold quality
substantia nigra pars reticulata	UBERON:0001966	84.04	silver quality
right frontal lobe	UBERON:0002810	83.98	gold quality
secondary oocyte	CL:0000655	83.96	gold quality
entorhinal cortex	UBERON:0002728	83.86	gold quality
cerebral cortex	UBERON:0000956	83.75	gold quality
ventral tegmental area	UBERON:0002691	83.71	silver quality
dorsolateral prefrontal cortex	UBERON:0009834	83.66	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	56.90
E-CURD-119	yes	49.14
E-ANND-3	no	5.59
E-GEOD-137537	no	3.25

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

64 targeting NOS1AP, 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-8485	100.00	77.57	4731
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-378G	99.71	64.90	1106

Literature-anchored findings (GeneRIF, showing 40)

• Characterization of the related mouse and rat proteins (PMID:11867766)
• Our findings indicate that CAPON gene may be a candidate susceptibility gene for schizophrenia in Chinese Han population, and also provide further support for the importance of NMDAR-mediated glutamatergic transmission in the etiology of schizophrenia. (PMID:15707951)
• study adds support to a role of CAPON in schizophrenia, produces new evidence implicating this gene in the etiology of bipolar disorder, and suggests a possible mechanism of action of CAPON in psychiatric illness (PMID:16146415)
• The present finding weakens the evidence that mutations or variation in the CAPON gene are causing genetic susceptibility to schizophrenia in European populations. (PMID:16202394)
• This genome-wide study identified NOS1AP (CAPON), a regulator of neuronal nitric oxide synthase, as a new target that modulates cardiac repolarization (PMID:16648850)
• NOS1AP variants influence QT interval (PMID:17565224)
• Strong effects of NOS1AP variants in diabetic individuals suggest that this patient subset may be particularly susceptible to genetic variants that influence myocardial depolarization and repolarization as manifest in the QT interval. (PMID:18235038)
• provide a rationale for the association of CAPON gene variants with extremes of the QT interval in human populations (PMID:18337493)
• Our results identified no single marker nor haplotype associated with schizophrenia, which did not suggest that CAPON was a susceptible site in the Chinese Han population. (PMID:18430503)
• Linkage and association studies from multiple samples drawn from different populations indicate that a schizophrenia susceptibility gene is located in the region of chromosome 1 containing NOS1AP. (PMID:18474209)
• Common variation in the NOS1AP gene is associated with reduced glucose-lowering effect and with increased mortality in users of sulfonylurea. (PMID:18551039)
• Single nucleotide polymorphisms are associated with incidence of diabetes mellitus in people who use calcium channel blockers. (PMID:18766325)
• Demonstrated that the common NOS1AP variant rs10494366 was associated with increased QT interval in healthy young adults. (PMID:18785031)
• A common variant (rs10494366T > G) within NOS1AP gene was associated with QT-interval duration. (PMID:18927126)
• study found significant association between eight SNPs in the NOS1AP gene region to schizophrenia (patients from a South American population isolate) and its clinical dimensions (PMID:19077434)
• We failed to provide evidence of an association between NOS1AP rs7538490 and type 2 diabetes, overweight, obesity or related quantitative metabolic phenotypes in large-scale studies of Danes (PMID:19111066)
• These data extend the association of genetic variants in NOS1AP with QT interval to a Black population…In addition, we identify a strong sex-interaction and the presence of a second independent site within NOS1AP associated with the QT interval. (PMID:19180230)
• sequence variations in NOS1AP were associated with baseline QT interval and the risk of sudden cardiac death in white US adults. (PMID:19204306)
• The minor alleles of both NOS1AP single nucleotide polymorphisms significantly potentiate the QTc prolonging effect of verapamil. (PMID:19247217)
• The A allele of rs12742393 appears to be a risk allele associated with schizophrenia that acts by enhancing transcription factor binding and increasing gene expression. (PMID:19255043)
• We do not know yet just how major a role NOS1AP will prove to play outside these Canadian families, but the replicated associations and the postmortem work suggest that the role may be more major than appreciated until now. (PMID:19339362)
• CPE mediates the effects of NOS1AP on dendrite morphology. (PMID:19553464)
• Study provided additional evidence for association between genetic variation within NOS1AP and SCD. (PMID:19643915)
• these findings support the hypothesis that NOS1 redistribution in injured myocardium requires the formation of a complex with the PDZ adaptor protein CAPON. (PMID:19800018)
• Association of NOS1AP genetic variants with risk for life-threatening arrhythmias suggests that this gene is a genetic modifier of the long-QT syndrome. (PMID:19822806)
• NOS1AP variants may not play a dominant role in susceptibility to type 2 diabetes, but a minor effect cannot be excluded. (PMID:19937226)
• the NOS1AP variant is associated with incidence of type 2 diabetes in calcium channel blocker users (PMID:19943157)
• The length of QT interval verify the importance of NOS1AP protein and to identify a SNP on chromosome 13 reaching genome-wide significance. (PMID:20031603)
• NOS1AP has a modest effect on ECG t-wave peak to t-wave end interval but is not related to T-wave morphology measures. (PMID:20215044)
• NOS1AP tag SNP genotype may provide an additional clinical dimension, which helps assess risk and choice of therapeutic strategies in LQTS. (PMID:20538168)
• Two non-synonymous NOS1AP variations, V37I and D423N were identified in two families, one with two siblings with Obsessive-Compulsive Disorder and the other with two brothers with autism spectrum disorders. (PMID:20602773)
• Data show that NOS1AP protein levels are altered in BA46 and cerebellum of patients with schizophrenia. (PMID:20605702)
• The genetic variant rs12143842 in NOS1AP is associated with QT interval duration in a Chinese population with Type 2 diabetes. (PMID:20722683)
• Common variations in or near CASQ2, GPD1L, and NOS1AP are associated with increased risk of sudden cardiac death in patients with coronary artery disease (PMID:21685173)
• relationship of nitric oxide synthase 1 adaptor protein (NOS1AP) polymorphism with serum creatinine level and occurrence of delayed graft function in kidney transplant recipients (PMID:21959512)
• NOS1AP rs203462 polymorphisms did not correlate with an increased risk of QT interval prolongation among kidney recipients. (PMID:21996201)
• Decreased NOS1AP expression in rs10494366 TT and rs10918594 CC homozygotes may underlie shorter repolarization times.Myocardial tissue for gene expression analysis was obtained from extracted cardiac implantable electronic device. (PMID:22019493)
• NOS1AP colocalizes with both SCRIB and VANGL1 along cellular protrusions in metastatic breast cancer cells, but does not colocalize with either SCRIB or VANGL1 at cell junctions in normal breast cells (PMID:22179838)
• Common variations in the NOS1AP gene are associated with a significant increase in the risk of drug-induced long QT syndrome. (PMID:22682551)
• This is the first study reporting that a variant of the NOS1AP gene is associated with PTSD. Our data also suggest that a genetic variant in NOS1AP may increase the susceptibility to severe depression in patients with PTSD and increased risk for suicide. (PMID:23146198)

Cross-species orthologs

13 orthologs

Organism	Symbol	Gene ID
danio_rerio	nos1apa	ENSDARG00000105071
mus_musculus	Nos1ap	ENSMUSG00000038473
rattus_norvegicus	Nos1ap	ENSRNOG00000042929
drosophila_melanogaster	Dab	FBGN0000414
drosophila_melanogaster	numb	FBGN0002973
drosophila_melanogaster	CG8312	FBGN0037720
drosophila_melanogaster	Aplip1	FBGN0040281
drosophila_melanogaster	CG42673	FBGN0261555
caenorhabditis_elegans		WBGENE00000894
caenorhabditis_elegans		WBGENE00001116
caenorhabditis_elegans		WBGENE00002176
caenorhabditis_elegans		WBGENE00003830
caenorhabditis_elegans		WBGENE00009930

Paralogs (11): MAPK8IP2 (ENSG00000008735), NUMBL (ENSG00000105245), MAPK8IP1 (ENSG00000121653), NUMB (ENSG00000133961), GULP1 (ENSG00000144366), DAB2 (ENSG00000153071), LDLRAP1 (ENSG00000157978), DAB1 (ENSG00000173406), FAM43B (ENSG00000183114), FAM43A (ENSG00000185112), C1orf226 (ENSG00000239887)

Protein

Protein identifiers

Carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase protein — O75052 (reviewed: O75052)

Alternative names: C-terminal PDZ ligand of neuronal nitric oxide synthase protein, Nitric oxide synthase 1 adaptor protein

All UniProt accessions (3): O75052, E9PIP8, E9PSG0

UniProt curated annotations — full annotation on UniProt →

Function. Adapter protein involved in neuronal nitric-oxide (NO) synthesis regulation via its association with nNOS/NOS1. The complex formed with NOS1 and synapsins is necessary for specific NO and synapsin functions at a presynaptic level. Mediates an indirect interaction between NOS1 and RASD1 leading to enhance the ability of NOS1 to activate RASD1. Competes with DLG4 for interaction with NOS1, possibly affecting NOS1 activity by regulating the interaction between NOS1 and DLG4. In kidney podocytes, plays a role in podosomes and filopodia formation through CDC42 activation.

Subunit / interactions. Interacts with the PDZ domain of NOS1 or the second PDZ domain of DLG4 through its C-terminus. Interacts with RASD1 and SYN1, SYN2 and SYN3 via its PID domain. Forms a ternary complex with NOS1 and RASD1. Forms a ternary complex with NOS1 and SYN1.

Subcellular location. Cell projection. Filopodium. Podosome.

Tissue specificity. Expressed in kidney glomeruli podocytes.

Disease relevance. Nephrotic syndrome 22 (NPHS22) [MIM:619155] A form of nephrotic syndrome, a renal disease clinically characterized by severe proteinuria, resulting in complications such as hypoalbuminemia, hyperlipidemia and edema. Kidney biopsies show non-specific histologic changes such as focal segmental glomerulosclerosis and diffuse mesangial proliferation. Some affected individuals have an inherited steroid-resistant form that progresses to end-stage renal failure. NPHS22 is an autosomal recessive, steroid-resistant form characterized by onset of progressive kidney dysfunction in infancy. The disease is caused by variants affecting the gene represented in this entry.

Polymorphism. Genetic variation in NOS1AP influences the electrocardiographic QT interval [MIM:610141]. The QT interval is defined as the time from the beginning of the Q wave to the end of the T wave, representing the duration of ventricular electrical activity. The QT interval, a measure of cardiac repolarization, is a genetically influenced quantitative trait with considerable medical relevance: both high and low values are associated with increased risk of cardiovascular morbidity and mortality.

Isoforms (3)

UniProt ID	Names	Canonical?
O75052-1	1	yes
O75052-2	2
O75052-3	3

RefSeq proteins (3): NP_001119532, NP_001158229, NP_055512* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006020	PTB/PI_dom	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR051133	Adapter_Engulfment-Domain	Family

Pfam: PF00640

UniProt features (20 total): modified residue 8, splice variant 3, region of interest 3, chain 1, domain 1, sequence variant 1, coiled-coil region 1, short sequence motif 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75052-F1	65.59	0.38

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 (8): 195, 266, 371, 374, 401, 417, 188, 192

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 205 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, FXR_IR1_Q6, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_POSITIVE_REGULATION_OF_POTASSIUM_ION_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_REGULATION_OF_CARDIAC_MUSCLE_CELL_MEMBRANE_REPOLARIZATION, NFKB_C, GOBP_CELL_JUNCTION_ORGANIZATION, GOBP_MUSCLE_CONTRACTION, GOBP_REGULATION_OF_CALCIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_MONOATOMIC_ION_TRANSPORT, GOBP_REACTIVE_NITROGEN_SPECIES_METABOLIC_PROCESS, GOBP_REGULATION_OF_HEART_RATE, GOBP_REGULATION_OF_CARDIAC_MUSCLE_CELL_ACTION_POTENTIAL

GO Biological Process (9): regulation of heart rate by chemical signal (GO:0003062), nitric oxide biosynthetic process (GO:0006809), regulation of nitric oxide biosynthetic process (GO:0045428), regulation of ventricular cardiac muscle cell membrane repolarization (GO:0060307), regulation of cardiac muscle cell action potential (GO:0098901), postsynaptic actin cytoskeleton organization (GO:0098974), positive regulation of potassium ion transmembrane transport (GO:1901381), regulation of calcium ion transmembrane transport via high voltage-gated calcium channel (GO:1902514), positive regulation of membrane repolarization during ventricular cardiac muscle cell action potential (GO:1905026)

GO Molecular Function (4): nitric-oxide synthase regulator activity (GO:0030235), signaling adaptor activity (GO:0035591), nitric-oxide synthase binding (GO:0050998), protein binding (GO:0005515)

GO Cellular Component (15): podosome (GO:0002102), nucleus (GO:0005634), mitochondrion (GO:0005739), cytosol (GO:0005829), caveola (GO:0005901), Z disc (GO:0030018), filopodium (GO:0030175), T-tubule (GO:0030315), sarcoplasmic reticulum membrane (GO:0033017), sarcolemma (GO:0042383), perinuclear region of cytoplasm (GO:0048471), glutamatergic synapse (GO:0098978), nuclear membrane (GO:0031965), cell projection (GO:0042995), anchoring junction (GO:0070161)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cytoplasm	3
actin-based cell projection	2
intracellular membrane-bounded organelle	2
regulation of heart rate	1
biosynthetic process	1
nitric oxide metabolic process	1
nitric oxide biosynthetic process	1
regulation of biosynthetic process	1
regulation of nitric oxide metabolic process	1
regulation of cardiac muscle cell membrane repolarization	1
ventricular cardiac muscle cell membrane repolarization	1
cardiac muscle cell action potential	1
regulation of action potential	1
actin cytoskeleton organization	1
postsynaptic cytoskeleton organization	1
positive regulation of potassium ion transport	1
potassium ion transmembrane transport	1
regulation of potassium ion transmembrane transport	1
positive regulation of cation transmembrane transport	1
calcium ion transmembrane transport via high voltage-gated calcium channel	1
regulation of calcium ion transmembrane transport	1
membrane repolarization during ventricular cardiac muscle cell action potential	1
regulation of membrane repolarization during ventricular cardiac muscle cell action potential	1
positive regulation of membrane repolarization during cardiac muscle cell action potential	1
nitric-oxide synthase activity	1
enzyme regulator activity	1
nitric-oxide synthase binding	1
protein-macromolecule adaptor activity	1
enzyme binding	1
binding	1
plasma membrane raft	1
I band	1
sarcolemma	1
endoplasmic reticulum membrane	1
sarcoplasmic reticulum	1
bounding membrane of organelle	1
plasma membrane	1
synapse	1
nucleus	1

Protein interactions and networks

STRING

1508 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NOS1AP	NOS1	P29475	994
NOS1AP	RASD1	Q9Y272	956
NOS1AP	DLG4	P78352	861
NOS1AP	SCRIB	Q14160	843
NOS1AP	SYN2	Q92777	759
NOS1AP	KCNH2	Q12809	747
NOS1AP	SYN1	P17600	720
NOS1AP	SNTA1	Q13424	695
NOS1AP	CPE	P16870	692
NOS1AP	KCNE1	P15382	668
NOS1AP	KCNQ1	P51787	666
NOS1AP	SCN5A	Q14524	647
NOS1AP	RGS4	P49798	638
NOS1AP	DTNBP1	Q96EV8	634
NOS1AP	DAOA	P59103	605

IntAct

225 interactions, top by confidence:

A	B	Type	Score
EAF1	ELL2	psi-mi:“MI:0914”(association)	0.840
PLK1	SPAG9	psi-mi:“MI:0914”(association)	0.790
PIP4K2A	AHCYL1	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
SCRIB	NOS1AP	psi-mi:“MI:0914”(association)	0.690
NOS1AP	SCRIB	psi-mi:“MI:0407”(direct interaction)	0.690
NOS1AP	FAM133A	psi-mi:“MI:0915”(physical association)	0.670
NOS1AP	NKAP	psi-mi:“MI:0915”(physical association)	0.660
NKAP	NOS1AP	psi-mi:“MI:0914”(association)	0.660
GPR156	PLD2	psi-mi:“MI:0914”(association)	0.640
PNN	CASC3	psi-mi:“MI:0914”(association)	0.640
NOS1AP	TRAF4	psi-mi:“MI:0915”(physical association)	0.560
TRAF4	NOS1AP	psi-mi:“MI:0915”(physical association)	0.560
PLK1	C1orf226	psi-mi:“MI:0914”(association)	0.560
PIP4K2A	AP3B1	psi-mi:“MI:0914”(association)	0.530
MDK	SETD1A	psi-mi:“MI:0914”(association)	0.530
SREK1IP1	KPNA5	psi-mi:“MI:0914”(association)	0.530
RHEX	NOS1AP	psi-mi:“MI:0914”(association)	0.530
DDX41	NOS1AP	psi-mi:“MI:0914”(association)	0.530
EPB41L1	AP3B1	psi-mi:“MI:0914”(association)	0.530

BioGRID (151): NOS1AP (Two-hybrid), FAM133A (Two-hybrid), NOS1AP (Affinity Capture-MS), NOS1AP (Affinity Capture-MS), AKNAD1 (Two-hybrid), NHP2 (Two-hybrid), NKAP (Two-hybrid), CT45A5 (Two-hybrid), RYBP (Two-hybrid), CKM (Two-hybrid), FYN (Two-hybrid), HSPD1 (Two-hybrid), PLAGL2 (Two-hybrid), PNP (Two-hybrid), NOS1AP (Proximity Label-MS)

ESM2 similar proteins: A0A0G2JUG7, A1L390, E9Q0S6, O08774, O14924, O15085, O43182, O54834, O54960, O60307, O75052, P57095, Q13009, Q3U1V8, Q3U214, Q3UHC7, Q4VAC9, Q5DU25, Q5JU85, Q5RBI7, Q5SXA9, Q5VWQ8, Q60610, Q64512, Q6AX33, Q6DN90, Q6NXJ0, Q6P0Q8, Q6P1I6, Q6ZMN7, Q76G19, Q76LL6, Q76M68, Q7T2V3, Q810W7, Q8CGE9, Q8IX03, Q8R0S2, Q8R4H2, Q8WYP3

Diamond homologs: O54960, O75052, Q8STF6, Q8SXX4, Q9D3A8

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 154 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
Neurexins and neuroligins	9	17.9×	7e-07
Assembly and cell surface presentation of NMDA receptors	6	15.4×	4e-04
RHOQ GTPase cycle	8	14.7×	2e-05
RND3 GTPase cycle	5	13.1×	2e-03
RHOJ GTPase cycle	5	10.1×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	9	36.8×	1e-09
protein localization to synapse	6	32.4×	8e-06
receptor clustering	6	26.4×	2e-05
regulation of postsynaptic membrane neurotransmitter receptor levels	6	20.9×	6e-05
establishment of protein localization	5	15.2×	2e-03
establishment of cell polarity	5	13.5×	3e-03
cell-cell adhesion	9	6.4×	1e-03
protein-containing complex assembly	8	6.4×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	63
Likely benign	7
Benign	33

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
995841	NM_014697.3(NOS1AP):c.428G>A (p.Cys143Tyr)	Pathogenic
995842	NM_014697.3(NOS1AP):c.345-3T>G	Pathogenic

SpliceAI

2654 predictions. Top by Δscore:

Variant	Effect	Δscore
1:162070279:CAAGG:C	donor_loss	1.0000
1:162070281:AGG:A	donor_loss	1.0000
1:162070282:GGTG:G	donor_loss	1.0000
1:162070283:GTG:G	donor_loss	1.0000
1:162070284:T:G	donor_loss	1.0000
1:162154403:A:AG	acceptor_gain	1.0000
1:162154404:G:GG	acceptor_gain	1.0000
1:162154404:GTAC:G	acceptor_gain	1.0000
1:162287339:T:TA	acceptor_gain	1.0000
1:162287339:TGCA:T	acceptor_loss	1.0000
1:162287341:CA:C	acceptor_loss	1.0000
1:162287342:A:AC	acceptor_loss	1.0000
1:162287342:A:AG	acceptor_gain	1.0000
1:162287342:AGTAT:A	acceptor_gain	1.0000
1:162287343:G:GA	acceptor_gain	1.0000
1:162287343:GT:G	acceptor_gain	1.0000
1:162287343:GTA:G	acceptor_gain	1.0000
1:162287343:GTAT:G	acceptor_gain	1.0000
1:162287343:GTATG:G	acceptor_gain	1.0000
1:162287434:AAG:A	donor_gain	1.0000
1:162287435:AG:A	donor_gain	1.0000
1:162287435:AGG:A	donor_loss	1.0000
1:162287436:GG:G	donor_gain	1.0000
1:162287437:G:GG	donor_gain	1.0000
1:162287437:GTAA:G	donor_loss	1.0000
1:162333015:AG:A	acceptor_gain	1.0000
1:162333016:GG:G	acceptor_gain	1.0000
1:162333169:TTCCA:T	donor_gain	1.0000
1:162343830:CCCAG:C	acceptor_gain	1.0000
1:162343831:CCA:C	acceptor_loss	1.0000

AlphaMissense

3319 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:162070196:T:C	Y7H	1.000
1:162070253:T:C	F26L	1.000
1:162070254:T:C	F26S	1.000
1:162070254:T:G	F26C	1.000
1:162070255:C:A	F26L	1.000
1:162070255:C:G	F26L	1.000
1:162070262:G:C	G29R	1.000
1:162070263:G:A	G29D	1.000
1:162070271:T:C	F32L	1.000
1:162070272:T:C	F32S	1.000
1:162070273:T:A	F32L	1.000
1:162070273:T:G	F32L	1.000
1:162070278:C:A	A34D	1.000
1:162154405:T:G	Y36D	1.000
1:162154411:G:A	G38R	1.000
1:162154411:G:C	G38R	1.000
1:162154412:G:A	G38E	1.000
1:162154412:G:T	G38V	1.000
1:162154418:T:C	L40P	1.000
1:162154432:C:A	P45T	1.000
1:162154432:C:T	P45S	1.000
1:162154433:C:A	P45H	1.000
1:162154433:C:G	P45R	1.000
1:162154441:A:G	R48G	1.000
1:162154441:A:T	R48W	1.000
1:162154442:G:C	R48T	1.000
1:162154442:G:T	R48M	1.000
1:162154443:G:C	R48S	1.000
1:162154443:G:T	R48S	1.000
1:162154450:A:T	I51F	1.000

dbSNP variants (sampled 300 via entrez): RS1000005367 (1:162339404 A>T), RS1000008070 (1:162175005 C>G,T), RS1000019285 (1:162225057 G>A), RS1000034896 (1:162113286 T>G), RS1000035194 (1:162155988 G>A), RS1000040312 (1:162202836 T>A), RS1000046608 (1:162253808 T>C), RS1000064429 (1:162234800 C>T), RS1000064924 (1:162323969 A>C,G), RS1000075212 (1:162366479 A>G), RS1000086289 (1:162161870 C>T), RS1000103295 (1:162116322 G>A), RS1000110623 (1:162280635 G>A), RS1000117097 (1:162332910 T>A), RS1000121146 (1:162137071 G>A)

Disease associations

OMIM: gene MIM:605551 | disease phenotypes: MIM:619155

GenCC curated gene-disease

Disease	Classification	Inheritance
nephrotic syndrome, type 22	Strong	Autosomal recessive

Mondo (3): nephrotic syndrome, type 22 (MONDO:0030895), long QT syndrome (MONDO:0002442), cardiac rhythm disease (MONDO:0007263)

Orphanet (0):

HPO phenotypes

25 total (25 of 25 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000096	Glomerular sclerosis
HP:0000100	Nephrotic syndrome
HP:0000365	Hearing impairment
HP:0001197	Abnormality of prenatal development or birth
HP:0001250	Seizure
HP:0001279	Syncope
HP:0001645	Sudden cardiac death
HP:0001664	Torsade de pointes
HP:0001688	Sinus bradycardia
HP:0002900	Hypokalemia
HP:0002907	Microscopic hematuria
HP:0003075	Hypoproteinemia
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0003774	Stage 5 chronic kidney disease
HP:0004308	Ventricular arrhythmia
HP:0004722	Thickened glomerular basement membrane
HP:0005135	Abnormal T-wave
HP:0005184	Prolonged QTc interval
HP:0007430	Generalized edema
HP:0012332	Abnormal autonomic nervous system physiology
HP:0012593	Nephrotic range proteinuria
HP:0031266	Podocyte foot process effacement
HP:0500018	Abnormal cardiac exercise stress test

GWAS associations

240 associations (top):

Study	Trait	p-value
GCST000004_1	QT interval	1.000000e-10
GCST000363_1	QT interval	3.000000e-45
GCST000363_2	QT interval	1.000000e-34
GCST000363_7	QT interval	2.000000e-78
GCST000364_1	QT interval	2.000000e-78
GCST000364_6	QT interval	7.000000e-33
GCST000444_1	QT interval	1.000000e-83
GCST000452_6	QT interval	2.000000e-10
GCST000561_15	Electrocardiographic traits	5.000000e-22
GCST000564_2	Electrocardiographic traits	7.000000e-10
GCST001580_2	QT interval	1.000000e-09
GCST001746_10	QT interval	2.000000e-15
GCST001762_636	Obesity-related traits	9.000000e-06
GCST002060_8	Word reading	5.000000e-06
GCST002500_1	QT interval	1.000000e-213
GCST002500_2	QT interval	7.000000e-61
GCST002500_3	QT interval	3.000000e-10
GCST002500_4	QT interval	1.000000e-08
GCST002500_49	QT interval	2.000000e-39
GCST002500_5	QT interval	3.000000e-129
GCST002500_50	QT interval	1.000000e-19
GCST002500_6	QT interval	9.000000e-14
GCST002500_7	QT interval	3.000000e-16
GCST002500_8	QT interval	1.000000e-37
GCST002500_9	QT interval	3.000000e-11
GCST002542_7	Electrocardiographic traits	4.000000e-18
GCST002575_5	Body mass index (change over time)	2.000000e-08
GCST004608_42	Granulocyte percentage of myeloid white cells	7.000000e-10
GCST004609_127	Monocyte percentage of white cells	9.000000e-12
GCST004863_44	Mosquito bite size	8.000000e-06

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0004682	QT interval
EFO:0004327	electrocardiography
EFO:0005300	word reading
EFO:0005937	longitudinal BMI measurement
EFO:0007997	granulocyte percentage of myeloid white cells
EFO:0007989	monocyte percentage of leukocytes
EFO:0008378	mosquito bite reaction size measurement
EFO:0009270	heel bone mineral density
EFO:0009764	eye colour measurement
EFO:0008398	T wave morphology measurement
EFO:0006501	carotid plaque build
EFO:0005091	monocyte count
EFO:0010701	mean reticulocyte volume

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

11 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs10494366	Toxicity	3	verapamil	Acquired Long QT Syndrome (aLQTS)
rs10494366	Toxicity	3	dolasetron;granisetron
rs10494366	Toxicity	3	Dihydropyridine derivatives
rs10494366	Efficacy	3	repaglinide	Diabetes Mellitus;Type 2
rs10494366	Toxicity	3	glyburide	Diabetes Mellitus;Type 2;Hypoglycemia
rs10494366	Toxicity	3	glimepiride	Diabetes Mellitus;Type 2;Hypoglycemia
rs10494366	Toxicity	3	glipizide	Diabetes Mellitus;Type 2;Hypoglycemia
rs10494366	Toxicity	3	digoxin	Shortened QT interval
rs10800397	Toxicity	3	amiodarone	Long QT Syndrome
rs10918594	Toxicity	3	verapamil	Acquired Long QT Syndrome (aLQTS)
rs10919035	Toxicity	3	amiodarone	Long QT Syndrome

PharmGKB variants

4 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs10494366	NOS1AP	3	2.75	8	dolasetron;granisetron;glyburide;glipizide;glimepiride;Dihydropyridine derivatives;digoxin;repaglinide;verapamil
rs10800397	NOS1AP	3	5.00	1	amiodarone
rs10918594	NOS1AP	3	0.00	1	verapamil
rs10919035	NOS1AP	3	3.00	1	amiodarone

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, increases methylation	3
dicrotophos	increases expression	1
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects expression, affects response to substance	1
VX-agent	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
coumarin	decreases phosphorylation	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Acetaminophen	decreases expression	1
Amiodarone	increases expression	1
Arsenic	affects methylation	1
Caffeine	affects phosphorylation	1
DEET	decreases expression	1
Estradiol	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	decreases methylation	1
Aflatoxin B1	decreases methylation	1
Gold Compounds	increases expression	1
Copper Sulfate	increases expression	1
S-Nitrosoglutathione	decreases expression	1
Magnetite Nanoparticles	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_WG47	PSMi007-A	Induced pluripotent stem cell	Female
CVCL_WJ38	PSMi008-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT00146822	PHASE4	COMPLETED	REFLEx Study (ENDOTAK RELIANCE G Evaluation of Handling and Electrical Performance
NCT00187239	PHASE4	COMPLETED	Reduce Ventricular Pacing in Dual Chamber Implantable Cardioverter Defibrillators Using AutoIntrinsic Conduction Search Study
NCT00247533	PHASE4	UNKNOWN	Cerebral Artery Stenosis, Coronary Artery Disease and Arrhythmia
NCT00282620	PHASE4	UNKNOWN	Magnesium to Reduce Implantable Cardioverter Defibrillator (ICD) Shocks and Improve Patient’s Quality of Life.
NCT00290056	PHASE4	UNKNOWN	Effect of Supplemental Intake of Omega-3 Polyunsaturated Fatty Acids on the Rate and Complexity of Spontaneously Occurring Ventricular and Supraventricular Arrhythmias in Patients With Implantable Cardioverter Defibrillator (ICD) - A Randomized Clinical Trial
NCT00313443	PHASE4	COMPLETED	Concentrations of Amiodarone in Fat Tissue During Chronic Treatment
NCT00457340	PHASE4	COMPLETED	Atorvastatin For The Reduction Of Ventricular Arrhythmias
NCT00507390	PHASE4	WITHDRAWN	Omega 3 Polyunsaturated Fatty Acid Supplements (PUFAs) and Microvolt T Wave Alternans (TWA) in Patients With Ventricular Arrhythmia
NCT00575523	PHASE4	COMPLETED	Atropine for Prevention of Dysrhythmias Caused by Percutaneous Ethanol Instillation for Hepatoma Therapy
NCT00579098	PHASE4	COMPLETED	The Use of Statins Following a Left Atrial Catheter Ablation Procedure to Prevent Atrial Fibrillation
NCT01613092	PHASE4	COMPLETED	Prevention of Arrhythmia Device Infection Trial (PADIT)
NCT01628666	PHASE4	COMPLETED	Prevention of Arrhythmia Device Infection Trial (PADIT)
NCT01717469	PHASE4	UNKNOWN	Safety and the Effects of Isolated Left Ventricular Pacing in Patients With Bradyarrhythmias
NCT01819064	PHASE4	COMPLETED	Heart Rate Response to Atropine Doses Less Than 0.1mg IV to Anesthetized Infants
NCT01834872	PHASE4	UNKNOWN	Safety and Feasibility of Arrhythmia Ablation Using the Amigo Remote Robotic System as Compared With Manual Ablation
NCT01841242	PHASE4	COMPLETED	Comparison of Alcoholic Chlorhexidine 2% Versus Alcoholic Povidone Iodine for Infections Prevention With Cardiac Resynchronization Therapy Device Implantation
NCT01991223	PHASE4	UNKNOWN	Dexmedetomidine for Catheter-related Bladder Discomfort
NCT02045173	PHASE4	COMPLETED	Automate Detection of Sleep Apnea by ApneascanTM
NCT02203630	PHASE4	TERMINATED	Phenylephrine Versus Norepinephrine for Septic Shock in Critically Ill Patients
NCT02565069	PHASE4	COMPLETED	Identification for the Treatment of Complex Arrhythmias
NCT03273634	PHASE4	COMPLETED	The Effect of Proton Pump Inhibition on Palpitations
NCT03289429	PHASE4	UNKNOWN	Antiarrhythmic and Cardioprotective Effects of Atorvastatin Versus Magnesium Sulfate in Cardiac Valve Replacement Surgery
NCT03895411	PHASE4	UNKNOWN	Efficacy and Safety of Sotalol in Children With Arrhythmia
NCT05486377	PHASE4	COMPLETED	Remimazolam vs Desflurane for General Anesthesia for Ablation of Arrhythmia
NCT06574555	PHASE4	COMPLETED	Norepinephrine ED90 Bolus After Spinal Anesthesia in Cesarean Section
NCT00000464	PHASE3	COMPLETED	Cardiac Arrest in Seattle: Conventional Versus Amiodarone Drug Evaluation (CASCADE)
NCT00000476	PHASE3	COMPLETED	Digitalis Investigation Group (DIG)
NCT00000480	PHASE3	COMPLETED	Multicenter Unsustained Tachycardia Trial (MUSTT)
NCT00000492	PHASE3	COMPLETED	Beta-Blocker Heart Attack Trial (BHAT)
NCT00000502	PHASE3	COMPLETED	Evaluation of SC-V Versus Conventional CPR
NCT00000517	PHASE3	COMPLETED	Boston Area Anticoagulation Trial for Atrial Fibrillation (BAATAF)
NCT00000518	PHASE3	COMPLETED	Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM)
NCT00000531	PHASE3	COMPLETED	Antiarrhythmics Versus Implantable Defibrillators (AVID)
NCT00000540	PHASE3	COMPLETED	Coronary Artery Bypass Graft (CABG) Patch Trial
NCT00000556	PHASE3	COMPLETED	Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM)
NCT00000561	PHASE3	COMPLETED	Mode Selection Trial in Sinus Node Dysfunction (MOST)