NKX1-1

Chr 4

NK1 homeobox 1

Also known as: HSPX153, NKX-1.1, SAX2

NCBI Gene: 54729 ENSG00000235608 UniProt: Q15270 OMIM: 617869

The protein is a transcription factor that regulates genes involved in energy homeostasis, with expression predominantly in the brainstem near serotonergic neurons. Mutations cause a severe neurodevelopmental disorder characterized by early-onset failure to thrive, lack of subcutaneous fat, and early lethality, following an autosomal recessive inheritance pattern. The gene shows moderate constraint against loss-of-function variants (pLI 0.71, LOEUF 0.72).

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a transcription factor that belongs to NKX family of homeodomain-containing proteins which are critical regulators of organ development. In mice, the orthologous gene is expressed predominantly in the brainstem, in the vicinity of serotonergic neurons, and is required for the coordinated crosstalk of factors involved in the maintenance of energy homeostasis. Mice with a knockout of the orthologous gene lack subcutaneous fat and intra-abdominal epididymal and mesenteric white adipose tissue two weeks after birth, and die within three weeks after birth. [provided by RefSeq, Jul 2017]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.72

Clinical Summary— NKX1-1

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.71) — some intolerance to loss-of-function variants.

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ClinVar Variants

1 total variants — no pathogenic classifications of 1 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.72LOEUF

pLI 0.715

Z-score 1.88

OE 0.00 (0.00–0.72)

Moderately constrained

Typical tolerance to LoF variation

Missense Constraint?

0.74Z-score

OE missense 0.78 (0.64–0.95)

67 obs / 86.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.72)

0≤0.351.4

Missense OE?0.78 (0.64–0.95)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 0 / 4.1Missense obs/exp: 67 / 86.3Syn Z: -0.41

This gene — mechanism propensity

0.3395th %ile

GOF

0.3193th %ile

LOF

0.81top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

1 submitted variants in ClinVar

ClinVar

Classification Summary

Benign1

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	0	0
Likely Benign	0	0
Benign	1	1
Total	1	1

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

View in ClinVar →

148 pathogenic / likely-pathogenic (of 164) ClinVar copy-number / structural variants overlap NKX1-1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →