GSX2

Chr 4AR

GS homeobox 2

Also known as: DMJDS2, GSH2

NCBI Gene: 170825 ENSG00000180613 UniProt: Q9BZM3 OMIM: 616253

GSX2 encodes a transcription factor that binds specific DNA sequences and regulates genes critical for brain development, particularly in specifying neuronal fates in the ventral telencephalon and striatal projection neurons. Autosomal recessive mutations cause diencephalic-mesencephalic junction dysplasia syndrome 2, a neurodevelopmental disorder affecting brain structures at the junction between the diencephalon and mesencephalon. This gene is essential for proper ventralization of brain progenitor cells and development of structures including the striatum and olfactory bulb interneurons.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Enables DNA-binding transcription factor activity, RNA polymerase II-specific and sequence-specific double-stranded DNA binding activity. Predicted to be involved in generation of neurons; olfactory bulb development; and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including nervous system development; positive regulation of Notch signaling pathway; and positive regulation of oligodendrocyte differentiation. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.831 OMIM phenotype

Clinical Summary— GSX2

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Gene-Disease Validity (ClinGen)

diencephalic-mesencephalic junction dysplasia syndrome 2 · ARModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.

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ClinVar Variants

37 VUS of 50 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.83LOEUF

pLI 0.257

Z-score 1.89

OE 0.26 (0.11–0.83)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.59Z-score

OE missense 0.87 (0.76–1.00)

143 obs / 164.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.26 (0.11–0.83)

0≤0.351.4

Missense OE?0.87 (0.76–1.00)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 2 / 7.6Missense obs/exp: 143 / 164.3Syn Z: -0.16

This gene — mechanism propensity

0.6551th %ile

GOF

0.4183th %ile

LOF

0.69top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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

ClinVar Variant Classifications

50 submitted variants in ClinVar

ClinVar

Classification Summary

VUS37

Likely Benign6

Benign7

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	37	0	0	37
Likely Benign	2	0	4	6
Benign	1	4	2	7
Total	40	4	6	50

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

View in ClinVar →

17 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap GSX2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →