NKX2-4

Summary

NKX2-4 (NK2 homeobox 4, HGNC:7837) is a protein-coding gene on chromosome 20p11.22, encoding Homeobox protein Nkx-2.4 (Q9H2Z4). Probable transcription factor.

Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in cell differentiation and regulation of transcription by RNA polymerase II. Predicted to be located in chromatin. Predicted to be active in nucleus.

Source: NCBI Gene 644524 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 80 total — 1 pathogenic
• MANE Select transcript: NM_033176

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7837
Approved symbol	NKX2-4
Name	NK2 homeobox 4
Location	20p11.22
Locus type	gene with protein product
Status	Approved
Aliases	NKX2.4
Ensembl gene	ENSG00000125816
Ensembl biotype	protein_coding
OMIM	607808
Entrez	644524

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000351817

RefSeq mRNA: 1 — MANE Select: NM_033176 NM_033176

CCDS: CCDS42855

Canonical transcript exons

ENST00000351817 — 2 exons

Exon	Start	End
ENSE00001365647	21396958	21397526
ENSE00001472930	21395365	21396533

Expression profiles

Bgee: expression breadth broad, 12 present calls, max score 84.32.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1677 / max 48.6944, expressed in 31 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
186601	0.1065	27
186600	0.0612	23

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.32	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.99	gold quality
right testis	UBERON:0004534	49.26	gold quality
testis	UBERON:0000473	48.77	gold quality
left testis	UBERON:0004533	48.27	gold quality
hypothalamus	UBERON:0001898	43.61	gold quality
ventricular zone	UBERON:0003053	40.13	gold quality
bone marrow cell	CL:0002092	39.99	gold quality
colonic epithelium	UBERON:0000397	37.20	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
adenohypophysis	UBERON:0002196	36.39	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
granulocyte	CL:0000094	35.31	gold quality
bone marrow	UBERON:0002371	33.70	gold quality
pituitary gland	UBERON:0000007	33.40	gold quality
skeletal muscle tissue	UBERON:0001134	33.38	gold quality
hindlimb stylopod muscle	UBERON:0004252	32.15	gold quality
prefrontal cortex	UBERON:0000451	31.29	gold quality
muscle tissue	UBERON:0002385	31.06	gold quality
sural nerve	UBERON:0015488	30.93	gold quality
primary visual cortex	UBERON:0002436	30.57	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	30.22	silver quality
superior frontal gyrus	UBERON:0002661	29.94	gold quality
stromal cell of endometrium	CL:0002255	29.87	gold quality
leukocyte	CL:0000738	29.68	gold quality
liver	UBERON:0002107	29.46	gold quality
monocyte	CL:0000576	29.33	gold quality
placenta	UBERON:0001987	29.28	gold quality
substantia nigra	UBERON:0002038	28.74	gold quality
duodenum	UBERON:0002114	28.14	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.00

Regulation

Is transcription factor: yes

JASPAR motifs

Motif	Name	Family
MA2003.1	NKX2-4	NK
MA2003.2	NKX2-4	NK

JASPAR matrix evidence (PMIDs): PMID:18585359

miRNA regulators (miRDB)

32 targeting NKX2-4, 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-150-5P	99.99	66.69	1976
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-5197-5P	99.64	69.08	1494
HSA-MIR-409-3P	99.50	66.33	1192
HSA-MIR-4325	99.49	72.20	1342
HSA-MIR-20B-3P	99.29	67.05	784
HSA-MIR-224-3P	98.91	68.42	1815
HSA-MIR-522-3P	98.91	68.56	1817
HSA-MIR-6780A-3P	98.42	67.49	1518
HSA-MIR-6509-3P	98.32	67.33	1343
HSA-MIR-6881-3P	98.04	68.24	1777
HSA-MIR-3921	97.81	67.45	1431
HSA-MIR-7111-3P	97.80	66.75	1467
HSA-MIR-7703	97.64	67.00	965
HSA-MIR-320E	97.49	65.96	865
HSA-MIR-4653-5P	97.22	67.72	1429
HSA-MIR-4445-5P	97.21	66.16	832
HSA-MIR-4436B-5P	96.71	68.37	1346

Literature-anchored findings (GeneRIF, showing 2)

• NKL Homeobox Genes NKX2-3 and NKX2-4 Deregulate Megakaryocytic-Erythroid Cell Differentiation in AML. (PMID:34768865)
• Functional characterization of 5p15.33 risk locus in uveal melanoma reveals rs452384 as a functional variant and NKX2.4 as an allele-specific interactor. (PMID:36459980)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
danio_rerio	nkx2.4a	ENSDARG00000075107
danio_rerio	nkx2.4b	ENSDARG00000104107
mus_musculus	Nkx2-4	ENSMUSG00000054160
rattus_norvegicus	Nkx2-4	ENSRNOG00000012647
drosophila_melanogaster	NK7.1	FBGN0024321
drosophila_melanogaster	HGTX	FBGN0040318
drosophila_melanogaster	scro	FBGN0287186
caenorhabditis_elegans	ceh-9	WBGENE00000434
caenorhabditis_elegans		WBGENE00000447
caenorhabditis_elegans		WBGENE00000450
caenorhabditis_elegans		WBGENE00000584

Paralogs (13): NKX3-2 (ENSG00000109705), NKX2-3 (ENSG00000119919), NKX2-2 (ENSG00000125820), NKX2-8 (ENSG00000136327), NKX2-1 (ENSG00000136352), NKX6-2 (ENSG00000148826), NKX6-1 (ENSG00000163623), NKX6-3 (ENSG00000165066), NKX3-1 (ENSG00000167034), NKX2-6 (ENSG00000180053), NKX2-5 (ENSG00000183072), NKX1-2 (ENSG00000229544), NKX1-1 (ENSG00000235608)

Protein

Protein identifiers

Homeobox protein Nkx-2.4 — Q9H2Z4 (reviewed: Q9H2Z4)

Alternative names: Homeobox protein NK-2 homolog D

All UniProt accessions (1): Q9H2Z4

UniProt curated annotations — full annotation on UniProt →

Function. Probable transcription factor.

Subcellular location. Nucleus.

Similarity. Belongs to the NK-2 homeobox family.

RefSeq proteins (1): NP_149416* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR020479	HD_metazoa	Domain
IPR050394	Homeobox_NK-like	Family

Pfam: PF00046

UniProt features (6 total): sequence conflict 2, chain 1, DNA-binding region 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H2Z4-F1	59.61	0.20

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 36 (showing top): chr20p11, GOMF_SEQUENCE_SPECIFIC_DNA_BINDING, MEISSNER_BRAIN_HCP_WITH_H3K27ME3, MEISSNER_NPC_HCP_WITH_H3K4ME2_AND_H3K27ME3, MIKKELSEN_MCV6_HCP_WITH_H3K27ME3, GOBP_POSITIVE_REGULATION_OF_TRANSCRIPTION_BY_RNA_POLYMERASE_II, GOMF_TRANSCRIPTION_REGULATOR_ACTIVITY, CBX7_TARGET_GENES, MIR32_5P, MIR92A_3P, MIR92B_3P, MIR367_3P, MIR363_3P, MIR25_3P, MIR4325

GO Biological Process (5): regulation of transcription by RNA polymerase II (GO:0006357), cell differentiation (GO:0030154), positive regulation of transcription by RNA polymerase II (GO:0045944), animal organ development (GO:0048513), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (6): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
transcription cis-regulatory region binding	2
cellular developmental process	1
positive regulation of DNA-templated transcription	1
anatomical structure development	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
nucleic acid binding	1
transcription regulator activity	1
binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

594 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NKX2-4	DCUN1D1	Q96GG9	900
NKX2-4	C8orf74	Q6P047	543
NKX2-4	KIZ	Q2M2Z5	507
NKX2-4	XRN2	Q9H0D6	445
NKX2-4	NKX2-2	O95096	381
NKX2-4	FOXB2	Q5VYV0	367
NKX2-4	SFTPB	P07988	354
NKX2-4	PAX1	P15863	351
NKX2-4	ZNF300	Q96RE9	348
NKX2-4	KAT14	Q9H8E8	347
NKX2-4	NKX6-3	A6NJ46	346
NKX2-4	LMX1B	O60663	346
NKX2-4	CRNKL1	Q9BZJ0	343
NKX2-4	LHX6	Q9UPM6	342
NKX2-4	IRX3	P78415	329

IntAct

14 interactions, top by confidence:

A	B	Type	Score
NOTO	NKX2-4	psi-mi:“MI:0915”(physical association)	0.560
ETV7	NFIB	psi-mi:“MI:2364”(proximity)	0.470
NKX2-5		psi-mi:“MI:0914”(association)	0.350
AIM2	DDX39A	psi-mi:“MI:0914”(association)	0.350
ARGLU1	PIAS2	psi-mi:“MI:2364”(proximity)	0.270
NFIB	BCL9	psi-mi:“MI:2364”(proximity)	0.270
PAX2	BCL9	psi-mi:“MI:2364”(proximity)	0.270
PAX8	BCL9	psi-mi:“MI:2364”(proximity)	0.270
SOX17	BCL9	psi-mi:“MI:2364”(proximity)	0.270
SP7	IGF2BP3	psi-mi:“MI:2364”(proximity)	0.270
TBR1	BCL9	psi-mi:“MI:2364”(proximity)	0.270
NKX2-4	NOTO	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (16): NOTO (Two-hybrid), NKX2-4 (Affinity Capture-MS), NKX2-4 (Affinity Capture-MS), NKX2-4 (Affinity Capture-MS), NKX2-4 (Proximity Label-MS), NKX2-4 (Proximity Label-MS), NKX2-4 (Proximity Label-MS), NKX2-4 (Proximity Label-MS), NKX2-4 (Proximity Label-MS), NKX2-4 (Proximity Label-MS), NKX2-4 (Proximity Label-MS), NKX2-4 (Affinity Capture-MS), NKX2-4 (Proximity Label-MS), NKX2-4 (Proximity Label-MS), NKX2-4 (Proximity Label-MS)

ESM2 similar proteins: A1YER7, A1YF08, A1YFD8, A1YFY3, A1YG85, A2D4P8, A2D4R4, A2D5I1, A2D649, A2T6H5, A2T6X6, A2T6Z0, A2T756, A2T7H5, A2T7J2, O35767, O43186, O88470, P06798, P09016, P10284, P10628, P17277, P17483, P18111, P23813, P31260, P31277, P31310, P42582, P43241, P43345, P47902, P52945, P52946, P52947, P52952, P57073, P58012, P70118

Diamond homologs: A1YF16, A1YG93, A2RU54, A2T764, A6NCS4, A6NHT5, G5EE18, O02786, O15522, O17319, O35767, O43763, O57601, O70218, O70584, O93590, O95096, P13297, P22711, P22808, P22809, P23410, P23441, P28360, P28361, P28362, P35548, P35993, P40764, P41936, P42581, P42582, P42583, P42584, P42586, P42587, P43687, P43688, P43697, P43698

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	76
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3068496	NC_000020.10:g.19434987_22528253del	Pathogenic

SpliceAI

210 predictions. Top by Δscore:

Variant	Effect	Δscore
20:21396956:A:AC	donor_gain	0.9900
20:21396957:C:CC	donor_gain	0.9900
20:21396959:TG:T	donor_gain	0.9800
20:21396957:CTTGA:C	donor_gain	0.9700
20:21396534:C:CC	acceptor_gain	0.9500
20:21396532:GACT:G	acceptor_gain	0.9400
20:21396533:ACTG:A	acceptor_gain	0.9400
20:21396531:AGAC:A	acceptor_gain	0.9300
20:21396530:GAGAC:G	acceptor_gain	0.9200
20:21396534:CTGG:C	acceptor_gain	0.9200
20:21396532:GA:G	acceptor_gain	0.8800
20:21396535:T:A	acceptor_gain	0.8800
20:21396529:GGAGA:G	acceptor_gain	0.8600
20:21396950:CCTCT:C	donor_loss	0.8500
20:21396951:CTCTC:C	donor_loss	0.8500
20:21396952:TCTCA:T	donor_loss	0.8500
20:21396953:CTCAC:C	donor_loss	0.8500
20:21396954:T:TA	donor_loss	0.8500
20:21396955:C:CC	donor_loss	0.8500
20:21396956:ACT:A	donor_loss	0.8500
20:21396957:C:CG	donor_loss	0.8500
20:21397023:T:TA	donor_gain	0.8500
20:21396533:AC:A	acceptor_loss	0.8300
20:21396534:C:A	acceptor_loss	0.8300
20:21396535:T:C	acceptor_loss	0.8300
20:21396530:GAGA:G	acceptor_gain	0.8100
20:21397324:T:TA	donor_gain	0.8100
20:21396548:C:T	acceptor_gain	0.7900
20:21396968:G:C	donor_gain	0.7900
20:21396536:G:C	acceptor_loss	0.7700

AlphaMissense

2250 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:21396241:T:A	K245N	1.000
20:21396241:T:G	K245N	1.000
20:21396242:T:A	K245I	1.000
20:21396243:T:C	K245E	1.000
20:21396247:C:A	K243N	1.000
20:21396247:C:G	K243N	1.000
20:21396248:T:A	K243M	1.000
20:21396248:T:G	K243T	1.000
20:21396249:T:C	K243E	1.000
20:21396249:T:G	K243Q	1.000
20:21396251:T:C	Y242C	1.000
20:21396252:A:C	Y242D	1.000
20:21396252:A:G	Y242H	1.000
20:21396254:C:G	R241P	1.000
20:21396254:C:T	R241Q	1.000
20:21396255:G:A	R241W	1.000
20:21396255:G:C	R241G	1.000
20:21396257:T:G	H240P	1.000
20:21396258:G:C	H240D	1.000
20:21396258:G:T	H240N	1.000
20:21396259:G:C	N239K	1.000
20:21396259:G:T	N239K	1.000
20:21396260:T:A	N239I	1.000
20:21396260:T:C	N239S	1.000
20:21396260:T:G	N239T	1.000
20:21396261:T:C	N239D	1.000
20:21396261:T:G	N239H	1.000
20:21396262:C:A	Q238H	1.000
20:21396262:C:G	Q238H	1.000
20:21396263:T:C	Q238R	1.000

dbSNP variants (sampled 300 via entrez): RS1000412367 (20:21396419 G>A,T), RS1000786079 (20:21395743 C>G,T), RS1002070964 (20:21399204 C>A), RS1002138717 (20:21397782 C>T), RS1004294591 (20:21397965 G>C), RS1004304488 (20:21397130 GGCC>G,GGCCGCC,GGCCGCCGCC), RS1004578699 (20:21395531 T>C), RS1004631099 (20:21395230 T>A), RS1005939756 (20:21398051 T>C), RS1006052606 (20:21397261 C>A,T), RS1006695680 (20:21395355 A>G), RS1007414763 (20:21398622 C>T), RS1007666168 (20:21395121 A>G), RS1007881249 (20:21398315 T>C), RS1008220612 (20:21397486 AGCTGAG>A)

Disease associations

OMIM: gene MIM:607808 | disease phenotypes: MIM:256450

GenCC curated gene-disease

Mondo (1): hyperinsulinemic hypoglycemia, familial, 1 (MONDO:0009734)

Orphanet (2): Autosomal dominant hyperinsulinism due to SUR1 deficiency (Orphanet:276575), Diazoxide-resistant focal hyperinsulinism due to SUR1 deficiency (Orphanet:276598)

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002479_15	Lupus nephritis in systemic lupus erythematosus	5.000000e-06
GCST007556_21	Autism spectrum disorder	3.000000e-07
GCST009391_521	Metabolite levels	4.000000e-06
GCST010988_318	Adult body size	8.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010117	pyruvate 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
FR900359	increases phosphorylation	1
butyraldehyde	increases expression	1
abrine	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Cadmium	increases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	decreases methylation	1

Clinical trials (associated diseases)

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