NKX6-2

protein-coding

NK6 homeobox 2, the group of NKL subclass homeoboxes and pseudogenes

Gene summary

Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in cell differentiation; regulation of DNA-templated transcription; and regulation of myelination. Predicted to act upstream of or within several processes, including central nervous system myelination; negative regulation of transcription by RNA polymerase II; and regulation of gliogenesis. Predicted to be located in chromatin. Predicted to be active in nucleus. Implicated in spastic ataxia 8. [provided by Alliance of Genome Resources, Jun 2026]

MANE transcript

NM_177400.3

Inheritance

ClinVar variants

P:24U:103B:55

Top phenotype

Spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy

gnomAD constraint

pLI —, LoF o/e 0.51

Max pathogenic AF

—

Genomic locus

chr10:132,783,179-132,786,147

External References & Databases

Ensembl (ENSG00000148826)

Transcript & Mutation Effects

hg38 • Region Span ~3.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033043

Submitter: PanelApp Australia

spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0033043

Submitter: Orphanet

spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033043

Submitter: Ambry Genetics

spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033043

Submitter: Labcorp Genetics (formerly Invitae)

spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033043

Submitter: G2P

Clinical Genomic Database (CGD)

Spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophyAR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 28575651

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NKX6-2 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 121

Inborn genetic diseasesTotal: 65

Spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophyTotal: 27

not specifiedTotal: 22

NKX6-2-related disorderTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_177400.3. 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	52 clinvar		53
missense	3 clinvar	2 clinvar	101 clinvar	3 clinvar		109
nonsense	4 clinvar	3 clinvar				7
start loss						0
frameshift	4 clinvar	7 clinvar	1 clinvar			12
splice donor/acceptor (+/-2bp)		1 clinvar				1
Total	11	13	103	55	0	182

Highest pathogenic variant AF is 0.000047669604

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_177400.3	RefSeq	NP_796374.2	3	MANE Select
ENST00000368592.8	Ensembl	ENSP00000357581.5	3	MANE Select
ENST00001143066.1	Ensembl	ENSP00000809429.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
nkx6.2	Danio rerio	Structure: primary motor neuron Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

nkx6.2

Danio rerio

Structure: primary motor neuron

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

negative regulation of transcription by RNA polymerase II
regulation of transcription, DNA-templated
negative regulation of cell fate commitment
positive regulation of cell fate commitment
regulation of transcription from RNA polymerase II promoter involved in spinal cord motor neuron fate specification

Molecular Function

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

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000368592
Coding exons: 3
Length: 1260
Individuals with no LoFs: 124947
Homozygous LoFs: 0
Heterozygous LoFs: 7
Defined: 124954
p: 0.0000280

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.139	120	116	1.04	0.00000549	1710
Missense (PolyPhen)		53	48.578	1.091		575
Synonymous	-0.196	57	55.1	1.03	0.00000278	593
Loss of Function	1.09	3	5.85	0.513	2.50e-7	86

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000028	0.000027	rare
South Asian	0.000034	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcription factor with repressor activity involved in the regulation of axon-glial interactions at myelin paranodes in oligodendrocytes. Binds to the consensus DNA sequence 5'- (A/T)TTAATGA-3'. In oligodendrocytes, binds to MBP and PLP1 promoter regions. {ECO:0000250|UniProtKB:D3Z4R4}.;

Recessive Scores

pRec: 0.168

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.282

Gene Damage Prediction

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