NKAPL

Summary

NKAPL (NFKB activating protein like, HGNC:21584) is a protein-coding gene on chromosome 6p22.1, encoding NKAP-like protein (Q5M9Q1). Transcriptional repressor of Notch-mediated signaling.

Predicted to enable chromatin binding activity. Predicted to be involved in regulation of gene expression. Predicted to be active in nucleus.

Source: NCBI Gene 222698 — RefSeq curated summary.

At a glance

• GWAS associations: 21
• Clinical variants (ClinVar): 51 total
• MANE Select transcript: NM_001007531

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21584
Approved symbol	NKAPL
Name	NFKB activating protein like
Location	6p22.1
Locus type	gene with protein product
Status	Approved
Aliases	bA424I5.1
Ensembl gene	ENSG00000189134
Ensembl biotype	protein_coding
Entrez	222698

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000343684

RefSeq mRNA: 1 — MANE Select: NM_001007531 NM_001007531

CCDS: CCDS34353

Canonical transcript exons

ENST00000343684 — 1 exons

Exon	Start	End
ENSE00001384451	28259297	28260958

Expression profiles

Bgee: expression breadth ubiquitous, 187 present calls, max score 92.53.

FANTOM5 (CAGE): breadth broad, TPM avg 1.5751 / max 72.0470, expressed in 646 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
66620	1.5264	631
66621	0.0488	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	92.53	gold quality
sperm	CL:0000019	89.72	gold quality
left testis	UBERON:0004533	88.71	gold quality
right testis	UBERON:0004534	88.17	gold quality
testis	UBERON:0000473	86.98	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	84.31	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.81	gold quality
pancreatic ductal cell	CL:0002079	81.01	silver quality
pons	UBERON:0000988	78.20	gold quality
hindlimb stylopod muscle	UBERON:0004252	76.96	gold quality
vena cava	UBERON:0004087	76.59	silver quality
medial globus pallidus	UBERON:0002477	76.46	silver quality
myocardium	UBERON:0002349	76.35	gold quality
gastrocnemius	UBERON:0001388	75.74	gold quality
muscle of leg	UBERON:0001383	75.38	gold quality
skeletal muscle tissue	UBERON:0001134	75.25	gold quality
globus pallidus	UBERON:0001875	75.06	silver quality
tendon of biceps brachii	UBERON:0008188	74.97	gold quality
left ventricle myocardium	UBERON:0006566	74.48	gold quality
muscle tissue	UBERON:0002385	74.42	gold quality
heart left ventricle	UBERON:0002084	73.80	gold quality
cardiac ventricle	UBERON:0002082	73.67	gold quality
inferior vagus X ganglion	UBERON:0005363	73.20	gold quality
primary visual cortex	UBERON:0002436	73.00	gold quality
cardiac muscle of right atrium	UBERON:0003379	72.77	gold quality
middle temporal gyrus	UBERON:0002771	72.41	silver quality
lateral nuclear group of thalamus	UBERON:0002736	72.39	silver quality
occipital lobe	UBERON:0002021	72.36	gold quality
ventral tegmental area	UBERON:0002691	72.19	silver quality
heart	UBERON:0000948	72.15	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-CURD-53	no	37.88
E-ANND-3	no	2.31

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

34 targeting NKAPL, 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-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-3609	99.52	69.89	2587
HSA-MIR-548AH-5P	99.52	69.73	2626
HSA-MIR-4489	99.50	65.56	785
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-208A-5P	99.42	70.83	1913
HSA-MIR-208B-5P	99.42	70.83	1952
HSA-MIR-5587-5P	99.07	68.58	838
HSA-MIR-5583-3P	99.06	65.68	1018
HSA-MIR-625-5P	99.02	68.64	2031
HSA-MIR-4260	98.78	65.37	848
HSA-MIR-5572	98.55	65.84	970
HSA-MIR-4778-5P	97.96	68.06	1634
HSA-MIR-4665-5P	97.91	67.69	1536
HSA-MIR-450A-2-3P	97.91	67.56	1459
HSA-MIR-6893-3P	97.79	64.91	1238
HSA-MIR-643	97.35	67.91	805
HSA-MIR-370-3P	97.09	64.92	1221
HSA-MIR-3126-5P	96.87	65.83	912
HSA-MIR-6875-5P	96.87	65.49	958
HSA-MIR-664B-5P	96.74	67.50	509

Literature-anchored findings (GeneRIF, showing 6)

• Genome-wide association study identifies a susceptibility locus for schizophrenia in Han Chinese at 11p11.2. (PMID:22037552)
• Fine-mapping analyses identified six NKAPL locus variants in a single haplotype block showing association with rheumatoid arthritis. (PMID:23223422)
• Study suggested that rs1635 in the NKAPL gene appeared to play a role in conferring susceptibility to schizophrenia (PMID:24972756)
• Overexpression of NKAPL in germline stem cells demonstrated that Nkapl induced changes in spermatogonial stem cell (SSC) markers and the reduction of differentiation factors through the Notch signaling pathway. (PMID:25875095)
• further evidence for the involvement of NKAPL polymorphisms in the development of schizophrenia. (PMID:26297123)
• Single nucleotide polymorphism in NKAPL is associated with atherosclerosis. (PMID:28095483)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	nkap	ENSDARG00000033450
mus_musculus	Nkapl	ENSMUSG00000059395
rattus_norvegicus	Nkapl	ENSRNOG00000056708
drosophila_melanogaster	CG6066	FBGN0039488
caenorhabditis_elegans	let-504	WBGENE00002696

Paralogs (1): NKAP (ENSG00000101882)

Protein

Protein identifiers

NKAP-like protein — Q5M9Q1 (reviewed: Q5M9Q1)

All UniProt accessions (1): Q5M9Q1

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional repressor of Notch-mediated signaling. Required for spermatogenesis.

Subunit / interactions. Interacts with RBPJ, CIRSR and HDAC3.

Subcellular location. Nucleus.

Similarity. Belongs to the NKAP family.

RefSeq proteins (1): NP_001007532* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009269	NKAP_C	Domain
IPR040466	NKAP	Family

Pfam: PF06047, PF15692

UniProt features (16 total): compositionally biased region 7, sequence variant 4, region of interest 2, modified residue 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5M9Q1-F1	60.21	0.09

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 (2): 23, 148

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 41 (showing top): GOBP_MALE_GAMETE_GENERATION, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM1, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, GOMF_CHROMATIN_BINDING, WAKABAYASHI_ADIPOGENESIS_PPARG_RXRA_BOUND_8D, EIF4E_DN, ZNF618_TARGET_GENES, MIR548AT_5P, MIR1275, MIR4778_5P, MIR4665_5P, MIR5587_5P, MIR4489, GSE13738_RESTING_VS_TCR_ACTIVATED_CD4_TCELL_UP, GSE13738_RESTING_VS_BYSTANDER_ACTIVATED_CD4_TCELL_UP

GO Biological Process (3): spermatogenesis (GO:0007283), regulation of gene expression (GO:0010468), cell differentiation (GO:0030154)

GO Molecular Function (2): chromatin binding (GO:0003682), protein binding (GO:0005515)

GO Cellular Component (1): nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
developmental process involved in reproduction	1
male gamete generation	1
gene expression	1
regulation of macromolecule biosynthetic process	1
cellular developmental process	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

824 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NKAPL	ZKSCAN4	Q969J2	723
NKAPL	ZKSCAN8	Q15776	646
NKAPL	ZSCAN9	O15535	614
NKAPL	ZSCAN16	Q9H4T2	608
NKAPL	PGBD1	Q96JS3	596
NKAPL	ZSCAN26	Q16670	574
NKAPL	ZSCAN31	Q96LW9	512
NKAPL	ZNF165	P49910	477
NKAPL	TSPAN18	Q96SJ8	468
NKAPL	ZKSCAN3	Q9BRR0	437
NKAPL	OR10K2	Q6IF99	434
NKAPL	ZNF438	Q7Z4V0	406
NKAPL	ZBTB41	Q5SVQ8	405
NKAPL	ZNF510	Q9Y2H8	405
NKAPL	ZNF646	O15015	399
NKAPL	ZNF546	Q86UE3	399

IntAct

33 interactions, top by confidence:

A	B	Type	Score
NKAP	NOS1AP	psi-mi:“MI:0914”(association)	0.660
NKAPL	DDX41	psi-mi:“MI:0915”(physical association)	0.560
ARL6IP4	NKAPL	psi-mi:“MI:0915”(physical association)	0.560
NKAPL	ZNF417	psi-mi:“MI:0915”(physical association)	0.560
NKAPL	CLK3	psi-mi:“MI:0915”(physical association)	0.560
NKAPL	SREK1IP1	psi-mi:“MI:0915”(physical association)	0.560
NKAPL	ZNF587	psi-mi:“MI:0915”(physical association)	0.560
NKAPL	NKAPD1	psi-mi:“MI:0915”(physical association)	0.560
NKAPL	TNFRSF10D	psi-mi:“MI:0915”(physical association)	0.400
NKAPL	CSNK2A2	psi-mi:“MI:0915”(physical association)	0.400
	NKAPL	psi-mi:“MI:0915”(physical association)	0.370
CUL2	ANXA2P2	psi-mi:“MI:0914”(association)	0.350
NKAP	C1orf226	psi-mi:“MI:0914”(association)	0.350
MAPK1	SEC16A	psi-mi:“MI:0914”(association)	0.350
NKAPL	DDX41	psi-mi:“MI:0915”(physical association)	0.000
ZNF417	NKAPL	psi-mi:“MI:0915”(physical association)	0.000
SREK1IP1	NKAPL	psi-mi:“MI:0915”(physical association)	0.000
ARL6IP4	NKAPL	psi-mi:“MI:0915”(physical association)	0.000
NKAPL	CLK3	psi-mi:“MI:0915”(physical association)	0.000
ZNF587	NKAPL	psi-mi:“MI:0915”(physical association)	0.000
NKAPD1	NKAPL	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (27): NKAPL (Affinity Capture-MS), NKAPL (Two-hybrid), NKAPL (Two-hybrid), NKAPL (Two-hybrid), NKAPL (Two-hybrid), NKAPL (Two-hybrid), NKAPL (Two-hybrid), ZNF587 (Two-hybrid), NKAPL (Affinity Capture-MS), NKAPL (Affinity Capture-MS), NKAPL (Affinity Capture-MS), NKAPL (Affinity Capture-MS), NKAPL (Affinity Capture-MS), TNFRSF10D (Affinity Capture-MS), CSNK2A2 (Affinity Capture-MS)

ESM2 similar proteins: A2RTL5, A6QLS2, B2RY56, O15042, P30189, P30640, P34433, P34594, P49756, Q10580, Q28C44, Q2TBE0, Q3LSS0, Q4V7C9, Q4X1D7, Q502P0, Q5M9I6, Q5M9Q1, Q5PQR4, Q5R7X2, Q5R814, Q5R8J6, Q5VTL8, Q5XHJ5, Q6AXY7, Q6DDA4, Q6DH74, Q6GLZ8, Q6NV83, Q6NWI1, Q6P7Y3, Q7L4I2, Q7SI59, Q7ZVW9, Q7ZYR8, Q80SY5, Q8GXN9, Q8IMP6, Q8N5F7, Q99LX5

Diamond homologs: Q4P4G8, Q4V7C9, Q55ED4, Q5M9Q1, Q5SZT7, Q8N5F7, Q9D0F4, Q9VB74

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	50
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

77 predictions. Top by Δscore:

Variant	Effect	Δscore
6:28260297:C:G	donor_gain	0.8900
6:28260296:GC:G	donor_gain	0.8600
6:28260282:AAG:A	donor_gain	0.7800
6:28260296:GCTGA:G	donor_gain	0.7000
6:28260280:TGA:T	donor_gain	0.6900
6:28260291:C:G	donor_gain	0.6900
6:28260301:G:GG	donor_gain	0.6800
6:28260347:TTGAC:T	donor_gain	0.6500
6:28260287:GC:G	donor_gain	0.6200
6:28260299:GA:G	donor_gain	0.6200
6:28260316:A:T	donor_gain	0.5800
6:28260253:G:GT	donor_gain	0.5600
6:28260295:GGC:G	donor_gain	0.5400
6:28260256:G:GG	donor_gain	0.5300
6:28260255:A:AG	donor_gain	0.4800
6:28260387:A:AG	donor_gain	0.4700
6:28260297:C:CG	donor_gain	0.4600
6:28260384:GT:G	donor_gain	0.4200
6:28260385:TT:T	donor_gain	0.4200
6:28259711:G:GT	donor_gain	0.4100
6:28260337:TG:T	donor_gain	0.4000
6:28260386:T:A	donor_gain	0.3900
6:28259742:A:T	donor_gain	0.3800
6:28260281:GAA:G	donor_gain	0.3800
6:28260300:A:AG	donor_gain	0.3700
6:28260304:T:A	donor_gain	0.3700
6:28259630:T:TA	acceptor_gain	0.3500
6:28260340:A:G	donor_gain	0.3500
6:28260577:G:GG	donor_gain	0.3500
6:28260184:G:GA	donor_gain	0.3400

AlphaMissense

2655 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:28260324:T:C	I318T	0.998
6:28260439:G:C	K356N	0.998
6:28260439:G:T	K356N	0.998
6:28260394:G:A	M341I	0.996
6:28260394:G:C	M341I	0.996
6:28260394:G:T	M341I	0.996
6:28260395:A:C	S342R	0.996
6:28260397:T:A	S342R	0.996
6:28260397:T:G	S342R	0.996
6:28260417:T:C	M349T	0.996
6:28260422:G:C	A351P	0.996
6:28260393:T:C	M341T	0.995
6:28260434:C:A	R355S	0.995
6:28260435:G:C	R355P	0.995
6:28260334:A:C	R321S	0.994
6:28260334:A:T	R321S	0.994
6:28260437:A:C	K356Q	0.994
6:28260376:A:C	E335D	0.993
6:28260376:A:T	E335D	0.993
6:28260432:T:C	L354P	0.993
6:28260442:G:C	E357D	0.993
6:28260442:G:T	E357D	0.993
6:28260447:A:C	Q359P	0.993
6:28260296:G:C	A309P	0.992
6:28260399:G:A	G343D	0.992
6:28260455:A:C	S362R	0.992
6:28260457:T:A	S362R	0.992
6:28260457:T:G	S362R	0.992
6:28260333:G:C	R321T	0.991
6:28260333:G:T	R321I	0.991

dbSNP variants (sampled 300 via entrez): RS1001245941 (6:28257706 A>G), RS1001676006 (6:28258016 C>T), RS1002705275 (6:28260800 G>A), RS1003970067 (6:28259258 C>T), RS1005643066 (6:28261150 T>G), RS1005732514 (6:28260633 A>G), RS1006888200 (6:28261215 T>C), RS1007559388 (6:28260941 GT>G,GTT), RS1010357235 (6:28258425 C>G,T), RS1011013323 (6:28259063 A>G), RS1011957292 (6:28259669 T>G), RS1012086969 (6:28261183 T>C), RS1013940372 (6:28257390 G>A), RS1014966600 (6:28259280 C>A,G), RS1015136755 (6:28257563 A>C,T)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

21 associations (top):

Study	Trait	p-value
GCST001299_1	Schizophrenia	7.000000e-12
GCST004521_112	Autism spectrum disorder or schizophrenia	3.000000e-26
GCST004521_115	Autism spectrum disorder or schizophrenia	3.000000e-16
GCST004521_166	Autism spectrum disorder or schizophrenia	4.000000e-24
GCST004521_212	Autism spectrum disorder or schizophrenia	5.000000e-14
GCST004521_23	Autism spectrum disorder or schizophrenia	2.000000e-11
GCST004521_6	Autism spectrum disorder or schizophrenia	2.000000e-15
GCST004521_7	Autism spectrum disorder or schizophrenia	2.000000e-15
GCST004521_73	Autism spectrum disorder or schizophrenia	8.000000e-11
GCST004521_77	Autism spectrum disorder or schizophrenia	1.000000e-19
GCST008921_4	Asthma and major depressive disorder	2.000000e-11
GCST008921_6	Asthma and major depressive disorder	1.000000e-09
GCST010002_50	Refractive error	4.000000e-34
GCST010142_16	Fish- and plant-related diet	2.000000e-10
GCST010142_19	Fish- and plant-related diet	4.000000e-10
GCST010142_34	Fish- and plant-related diet	7.000000e-09
GCST010142_35	Fish- and plant-related diet	8.000000e-09
GCST010142_42	Fish- and plant-related diet	1.000000e-08
GCST010142_7	Fish- and plant-related diet	3.000000e-12
GCST010702_75	Subcortical volume (MOSTest)	3.000000e-11
GCST010703_272	Brain morphology (MOSTest)	7.000000e-16

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008111	diet measurement
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

7 total (human), top 7 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, increases methylation	2
bisphenol A	affects cotreatment, increases methylation, decreases methylation	1
sodium arsenite	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Benzo(a)pyrene	affects methylation	1
Tobacco Smoke Pollution	increases expression	1
Aflatoxin B1	increases methylation	1

Clinical trials (associated diseases)

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