LHX6

Chr 9

LIM homeobox 6

Also known as: LHX6.1, hLHX6

NCBI Gene: 26468ENSG00000106852UniProt: Q9UPM6

This gene encodes a member of a large protein family that contains the LIM domain, a unique cysteine-rich zinc-binding domain. The encoded protein has tandem LIM domains as well as a DNA-binding homeodomain. The protein functions as a transcription factor involved in embryogenesis and head development and is highly expressed in neural crest derived mesenchyme cells. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jan 2017]

0
Active trials
28
Pathogenic / LP
69
ClinVar variants
6
Pubs (1 yr)
2.9
Missense Z
0.33
LOEUF· LoF intolerant
Clinical Summary— LHX6
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
28 Pathogenic / Likely Pathogenic· 40 VUS of 69 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.33LOEUF
pLI 0.966
Z-score 3.65
OE 0.10 (0.04–0.33)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

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.
2.93Z-score
OE missense 0.46 (0.39–0.54)
104 obs / 228.4 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.10 (0.04–0.33)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.46 (0.39–0.54)
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.0.87
0≤1.21.6
LoF obs/exp: 2 / 19.3Missense obs/exp: 104 / 228.4Syn Z: 1.01
DN
0.3892th %ile
GOF
0.3986th %ile
LOF
0.79top 5%

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

LOFprediction above median · LOEUF 0.33

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

69 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic27
Likely Pathogenic1
VUS40
Likely Benign1
27
Pathogenic
1
Likely Pathogenic
40
VUS
1
Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
27
0
27
Likely Pathogenic
0
0
1
0
1
VUS
0
39
1
0
40
Likely Benign
0
0
1
0
1
Benign
0
0
0
0
0
Total03930069

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

View in ClinVar →

Protein Context — Lollipop Plot

LHX6 · protein map & ClinVar variants

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Landmark / reviewRecent case evidence
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
UGT8/GalCer-dependent resistance of breast cancer cells to drug-induced apoptosis is potentially regulated by the LIM/homeobox protein LHX6.
Suchanski J et al.·Sci Rep
2026
Comparative distribution of the hypothalamic neurons activated during wakefulness and paradoxical (REM) sleep using male TRAP2-red mice: contribution of orexin, MCH, Lhx6 and a new marker Meis2.
Chancel A et al.·Sleep
2025
Dysfunctional LHX6 pallido-subthalamic projections mediate epileptic events in a mouse model of Leigh syndrome.
Sánchez-Benito L et al.·J Clin Invest
2025Open AccessFunctional
FOXR2 Targets LHX6+/DLX+ Neural Lineages to Drive Central Nervous System Neuroblastoma.
Jessa S et al.·Cancer Res
2025Open Access
Modulation of pain sensitivity by Ascl1- and Lhx6-dependent GABAergic neuronal function in streptozotocin diabetic mice.
Hwang SM et al.·Mol Ther
2025Open Access
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