LHX2

Chr 9

LIM homeobox 2

Also known as: LH2, hLhx2

NCBI Gene: 9355ENSG00000106689UniProt: P50458OMIM: 603759

LHX2 encodes a transcription factor that regulates cell differentiation in developing lymphoid and neural tissues and acts as a transcriptional activator. Mutations cause autosomal dominant developmental abnormalities affecting the nervous system and other organ systems. The gene is highly constrained against loss-of-function variants (pLI 0.99, LOEUF 0.22), indicating that even single functional copies are critical for normal development.

OMIMResearchSummary from UniProt
LOFmechanismLOEUF 0.22
Clinical Summary— LHX2
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Gene-Disease Validity (ClinGen)
complex neurodevelopmental disorder · ADStrong

Strong evidence — appropriate for clinical testing

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Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.
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ClinVar Variants
35 unique Pathogenic / Likely Pathogenic· 58 VUS of 101 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.22LOEUF
pLI 0.988
Z-score 3.39
OE 0.00 (0.00–0.22)
Highly constrained

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

Missense Constraint
2.27Z-score
OE missense 0.59 (0.51–0.68)
143 obs / 242.7 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.00 (0.00–0.22)
0≤0.351.4
Missense OE0.59 (0.51–0.68)
0≤0.61.4
Synonymous OE1.14
0≤1.21.6
LoF obs/exp: 0 / 13.4Missense obs/exp: 143 / 242.7Syn Z: -1.17
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
moderateLHX2-related neurodevelopmental disorder with or without microcephalyLOFAD
DN
0.3892th %ile
GOF
0.3887th %ile
LOF
0.85top 5%

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

LOFprediction above median · LOEUF 0.22

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

101 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic33
Likely Pathogenic2
VUS58
Likely Benign5
Benign2
33
Pathogenic
2
Likely Pathogenic
58
VUS
5
Likely Benign
2
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
4
2
27
0
33
Likely Pathogenic
1
0
1
0
2
VUS
5
50
2
1
58
Likely Benign
0
2
0
3
5
Benign
0
1
0
1
2
Total1055305100

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

View in ClinVar →

Protein Context — Lollipop Plot

LHX2 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
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
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