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; 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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophyMIM #617560

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.31

LOEUF

LOF

Mechanism· G2P

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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

Background carrier burden — how many people carry a rare variant somewhere in NKX6-2?

gnomAD v4 · ~730k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 170

518 rare PASS variants

Rare truncating (LoF)

1 in 1,800

73 rare PASS variants

Rare synonymous (reference)

1 in 260

271 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NKX6-2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 190	1 in 2,200
South Asian	~43k	1 in 150	1 in 460
Remaining (unassigned)	~30k	1 in 120	1 in 1,600
European (Finnish)	~26k	1 in 270	1 in 3,800
Admixed American	~22k	1 in 97	1 in 1,200
African / African American	~21k	1 in 92	1 in 2,000
East Asian	~20k	1 in 110	1 in 2,200
Ashkenazi Jewish	~13k	1 in 500	1 in 1,600
Middle Eastern	~2,884	1 in 120	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 2 of 3 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 3.? see exons ↓