NKX6-2

Chr 10AR

NK6 homeobox 2

Also known as: GTX, NKX6.2, NKX6B, SPAX8

NCBI Gene: 84504ENSG00000148826UniProt: Q9C056OMIM: 605955

This transcription factor regulates oligodendrocyte differentiation and axon-glial interactions at myelin paranodes by binding to MBP and PLP1 promoter regions. Biallelic mutations cause spastic ataxia 8, an autosomal recessive disorder characterized by hypomyelinating leukodystrophy. The pathogenic mechanism involves disrupted myelination due to impaired transcriptional regulation of key myelin proteins.

OMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismARLOEUF 1.311 OMIM phenotype
Clinical Summary— NKX6-2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.03) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
25 unique Pathogenic / Likely Pathogenic· 48 VUS of 100 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
1.31LOEUF
pLI 0.029
Z-score 1.09
OE 0.51 (0.23–1.31)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
-0.14Z-score
OE missense 1.04 (0.89–1.21)
120 obs / 115.8 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.51 (0.23–1.31)
0≤0.351.4
Missense OE1.04 (0.89–1.21)
0≤0.61.4
Synonymous OE1.03
0≤1.21.6
LoF obs/exp: 3 / 5.8Missense obs/exp: 120 / 115.8Syn Z: -0.20
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
strongNKX6-2-related progressive spastic ataxia and hypomyelinationLOFAR

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

DN
0.74top 25%
GOF
0.4085th %ile
LOF
0.58top 25%

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

100 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic21
Likely Pathogenic4
VUS48
Likely Benign26
Benign1
21
Pathogenic
4
Likely Pathogenic
48
VUS
26
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
20
0
21
Likely Pathogenic
4
0
0
0
4
VUS
0
45
3
0
48
Likely Benign
0
1
4
21
26
Benign
0
0
0
1
1
Total5462722100

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

NKX6-2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Keeping IPMNs in Check: A Novel Role for the Transcription Factor NKX6-2 in Preserving an Indolent Cell Identity in Pancreatic Cystic Lesions.
Ben-Shmuel A et al.·Cancer Discov
2023
Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential.
Sans M et al.·Cancer Discov
2023
A homozygous missense variant in the homeobox domain of the NKX6-2 results in progressive spastic ataxia type 8 associated with lower limb weakness and neurological manifestations.
Almatrafi A et al.·J Gene Med
2020
Expanding the clinical and neuroimaging features of NKX6-2-related hereditary spastic ataxia type 8.
Hosseini Bereshneh A et al.·Eur J Med Genet
2020
Genetic and phenotypic characterization of NKX6-2-related spastic ataxia and hypomyelination.
Chelban V et al.·Eur J Neurol
2020
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients