GSX2

protein-coding

GS homeobox 2, the group of HOXL subclass homeoboxes

Gene summary

Enables DNA-binding transcription factor activity, RNA polymerase II-specific and sequence-specific double-stranded DNA binding activity. Predicted to be involved in DNA-templated transcription; nervous system 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, Jun 2026]

MANE transcript

NM_133267.3

Inheritance

ClinVar variants

U:39B:6

Top phenotype

GSX2-related disorder

gnomAD constraint

pLI —, LoF o/e 0.26

Max pathogenic AF

—

Genomic locus

chr4:54,099,523-54,102,498

External References & Databases

Ensembl (ENSG00000180613)

Transcript & Mutation Effects

hg38 • Region Span ~3.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

diencephalic-mesencephalic junction dysplasia syndrome 2LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0020762

Submitter: Labcorp Genetics (formerly Invitae)

diencephalic-mesencephalic junction dysplasia syndrome 2MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0020762

Submitter: PanelApp Australia

diencephalic-mesencephalic junction dysplasia syndrome 2MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0020762

Submitter: ClinGen

The *GSX2* gene encodes a transcription factor thought to be involved in brain development. *GSX2* was first reported in relation to autosomal recessive Diencephalic-Mesencephalic Junction Dysplasia Syndrome 2 in 2019 (De Mori et al., PMID: 31412107). Phenotypes onset at birth and can include severe global developmental delay, spastic tetraplegia, abnormal basal ganglia morphology, dystonia, decreased thalamic volume, absent speech, feeding difficulties in infancy, inability to walk, and hypoplasia of the olfactory bulb. Evidence supporting this gene-disease relationship include case-level data and experimental data. The genetic evidence in this curation includes three variants, one nonsense and two missense, from three probands, reported in two publications (De Mori et al., PMID: 31412107 and Ürel-Demir et al., PMID: 39119454). The mechanism of disease is presumed to be reduced or loss of function. This gene-disease relationship is also supported by experimental evidence. A *GSX2* knockout mouse model demonstrated a reduced lateral ganglionic eminence size in the forebrain at developmental stages E12.5 to E17.5, similar to basal ganglia agenesis observed in patients (PMID: 9398437). A missense mouse model shows brain patterning defect and abnormal GSX2 brain expression in the mutants (PMID: 39882631). Zebrafish expression data reveals GSX2 expression in the brain during embryonic development (PMID: 36184733). Zebrafish functional alteration evidence reveals that mutants have abnormal oligodendrocyte lineage cell development (PMID: 41491310). This gene-disease pair was originally evaluated by the Cerebral Palsy GCEP on February 27th, 2023. It was re-evaluated on May 18th, 2026. As a result of this reevaluation, the classification increased from Limited to Moderate with the addition of genetic evidence (PMID: 39119454), a mouse model (PMID: 39882631), expression-level data (PMID: 36184733), and functional alteration evidence (PMID: 41491310) (SOP Version 12).

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GSX2 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 38

not providedTotal: 3

GSX2-related disorderTotal: 2

Diencephalic-mesencephalic junction dysplasia syndrome 2Total: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_133267.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				4 clinvar		4
missense			38 clinvar	2 clinvar		40
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	39	6	0	45

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 4 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_133267.3	RefSeq	NP_573574.2	2	MANE Select
ENST00000326902.7	Ensembl	ENSP00000319118.2	2	MANE Select
ENST00000503800.1	Ensembl	ENSP00000422213.1	2	Standard
ENST00000503800.2	Ensembl	ENSP00000422213.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

regulation of respiratory gaseous exchange by neurological system process
regulation of transcription by RNA polymerase II
spinal cord association neuron differentiation
hindbrain morphogenesis
forebrain dorsal/ventral pattern formation

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA binding
sequence-specific DNA binding

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000326902
Coding exons: 2
Length: 2983
Individuals with no LoFs: 125674
Homozygous LoFs: 0
Heterozygous LoFs: 59
Defined: 125733
p: 0.000235

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.592	143	164	0.870	0.00000746	1912
Missense (PolyPhen)		41	67.384	0.60845		773
Synonymous	-0.157	78	76.3	1.02	0.00000372	648
Loss of Function	1.89	2	7.62	0.262	3.33e-7	82

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.0032	0.0032	notable
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000089	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: During telencephalic development, causes ventralization of pallial progenitors and, depending on the developmental stage, specifies different neuronal fates. At early stages, necessary and sufficient to correctly specify the ventral lateral ganglionic eminence (LGE) and its major derivatives, the striatal projection neurons. At later stages, may specify LGE progenitors toward dorsal LGE fates, including olfactory bulb interneurons (By similarity). Transcription factor that binds 5'-CNAATTAG-3' DNA sequence. {ECO:0000250|UniProtKB:P31316}.;

Recessive Scores

pRec: 0.137

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.421

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium