NKX6-2

Chr 10AR

NK6 homeobox 2

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

NCBI Gene: 84504ENSG00000148826UniProt: Q9C056

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; pancreatic A cell differentiation; and regulation of oligodendrocyte differentiation. Predicted to be located in chromatin. Predicted to be active in nucleus. Implicated in spastic ataxia 8. [provided by Alliance of Genome Resources, Apr 2025]

Primary Disease Associations & Inheritance

Spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophyMIM #617560
AR
100
ClinVar variants
18
Pathogenic / LP
0.03
pLI score
0
Active trials
Clinical Summary— NKX6-2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.03) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
18 Pathogenic / Likely Pathogenic· 49 VUS of 100 total submissions
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.14Z-score
OE missense 1.04 (0.89–1.21)
120 obs / 115.8 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.51 (0.23–1.31)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.04 (0.89–1.21)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.03
0≤1.21.6
LoF obs/exp: 3 / 5.8Missense obs/exp: 120 / 115.8Syn Z: -0.20

ClinVar Variant Classifications

100 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic14
Likely Pathogenic4
VUS49
Likely Benign29
Benign3
Conflicting1
14
Pathogenic
4
Likely Pathogenic
49
VUS
29
Likely Benign
3
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
1
11
0
14
Likely Pathogenic
1
2
1
0
4
VUS
1
45
2
1
49
Likely Benign
0
0
5
24
29
Benign
0
0
3
0
3
Conflicting
—1
Total4482225100

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.

Gene2Phenotype Curations

NKX6-2-related progressive spastic ataxia and hypomyelination

strong
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
NK6 HOMEOBOX 2; NKX6-2
MIM #605955 · *

Spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy

MIM #617560

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — NKX6-2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Expanding the genetic heterogeneity of intellectual disability.
Anazi S et al.·Hum Genet
2017
Identification of spatially-resolved markers of malignant transformation in Intraductal Papillary Mucinous Neoplasms.
Agostini A et al.·Nat Commun
2024
Expanding the clinical and genetic spectra of NKX6-2-related disorder.
Baldi C et al.·Clin Genet
2018
Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination.
Chelban V et al.·Am J Hum Genet
2017
Genetic and phenotypic characterization of NKX6-2-related spastic ataxia and hypomyelination.
Chelban V et al.·Eur J Neurol
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
2020Case report
Neuroimaging to Genotype: Delineating the Spectrum of Disorders With Deficient Myelination in the Indian Population.
Kaur N et al.·Am J Med Genet A
2025
NK6 Homeobox 2 Regulated Gastrokin-2 Suppresses Gastric Cancer Cell Proliferation and Invasion via Akt Signaling Pathway.
Dai J et al.·Cell Biochem Biophys
2021
Biallelic mutations in the homeodomain of NKX6-2 underlie a severe hypomyelinating leukodystrophy.
Dorboz I et al.·Brain
2017
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
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools