NKX6-2

Chr 10AR

NK6 homeobox 2

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

NCBI Gene: 84504 ENSG00000148826 UniProt: Q9C056 OMIM: 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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.311 OMIM phenotype

Clinical Summary— NKX6-2

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Population Constraint (gnomAD)

Low constraint (pLI 0.03) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

23 unique Pathogenic / Likely Pathogenic· 101 VUS of 188 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — NKX6-2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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 OE?0.51 (0.23–1.31)

0≤0.351.4

Missense OE?1.04 (0.89–1.21)

0≤0.61.4

Synonymous OE?1.03

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

This gene — mechanism propensity

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

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

188 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11

Likely Pathogenic12

VUS101

Likely Benign56

Benign6

Conflicting1

Pathogenic

Likely Pathogenic

101

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	8	3	0	0	11
Likely Pathogenic	10	2	0	0	12
VUS	1	98	1	1	101
Likely Benign	0	3	7	46	56
Benign	0	1	4	1	6
Conflicting	—				1
Total	19	107	12	48	187

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

View in ClinVar →

98 pathogenic / likely-pathogenic (of 118) ClinVar copy-number / structural variants overlap NKX6-2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →