NKX2-4

protein-coding

NK2 homeobox 4, the group of NKL subclass homeoboxes and pseudogenes

Gene summary

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. [provided by Alliance of Genome Resources, Jul 2025]

Previous symbols:

NKX2D

MANE transcript

NM_033176.2

Inheritance

—

ClinVar variants

U:75B:3

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.7

Max pathogenic AF

—

Genomic locus

chr20:21,395,365-21,397,526

External References & Databases

Ensembl (ENSG00000125816)

Transcript & Mutation Effects

hg38 • Region Span ~2.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NKX2-4 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 75

not providedTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_033176.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				1 clinvar	1 clinvar	2
missense			75 clinvar	1 clinvar		76
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	75	2	1	78

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 3 of 3 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_033176.2	RefSeq	NP_149416.1	2	MANE Select
ENST00000351817.5	Ensembl	ENSP00000345147.4	2	MANE Select
ENST00001131750.1	Ensembl	ENSP00000808178.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

regulation of transcription by RNA polymerase II
multicellular organism development
biological_process
cell differentiation
positive regulation of transcription by RNA polymerase II

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
molecular_function
DNA-binding transcription factor activity
sequence-specific DNA binding

Cellular Component

cellular_component
nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000351817
Coding exons: 2
Length: 2662
Individuals with no LoFs: 122246
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 122250
p: 0.0000164

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0799	115	113	1.02	0.00000528	2169
Missense (PolyPhen)		48	55.775	0.8606		871
Synonymous	-1.49	66	52.3	1.26	0.00000272	774
Loss of Function	0.666	4	5.72	0.699	2.46e-7	92

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00012	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000092	0.0000090	rare
South Asian	0.000034	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probable transcription factor.;

Recessive Scores

pRec: 0.139

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.530

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium