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GeneE
10 sources retrieved Β· Most recent: April 2026 Β· Index updated 14 days ago
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NTNG2
netrin G2
Chromosome 9 Β· 9q34.13
NCBI Gene: 84628Ensembl: ENSG00000196358.13HGNC: HGNC:14288UniProt: Q96CW9
27PubMed Papers
21Diseases
0Drugs
8Pathogenic Variants
CLINICAL
OMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
plasma membraneprotein bindingcell-cell adhesion mediator activityregulation of neuron migrationneurodevelopmental disorder with behavioral abnormalities, absent speech, and hypotoniaNeurodevelopmental disordercomplex neurodevelopmental disorderAreflexia
✦AI Summary

NTNG2 encodes netrin-G2, a membrane-anchored presynaptic cell adhesion protein critical for neuronal circuit development and synaptic organization 1. The protein promotes neurite outgrowth and is essential for proper neuronal morphology and cortical migration, as demonstrated by severe developmental defects following NTNG2 knockdown in cultured hippocampal neurons and in vivo models 2. NTNG2 functions through CaMKII signaling pathways, with mutations leading to decreased CaMKII activity and reduced excitatory postsynaptic transmission 3. Loss-of-function mutations cause a distinct neurodevelopmental disorder characterized by global developmental delay, severe intellectual disability, hypotonia, autistic features, and behavioral abnormalities 14. Homozygous frameshift variants result in Rett-like phenotypes with areflexia, demonstrating the protein's critical role in normal neurodevelopment 2. Additionally, reduced NTNG2 mRNA expression has been observed in the temporal lobe of individuals with schizophrenia and bipolar disorder, suggesting broader involvement in neuropsychiatric conditions 5. The protein's role in synaptic plasticity and NMDAR-mediated signaling may explain the autism spectrum disorder phenotypes associated with its dysfunction 4.

Sources cited
1
NTNG2 encodes netrin-G2, a membrane-anchored presynaptic protein causing neurodevelopmental disorder with intellectual disability
PMID: 31668703
2
NTNG2 knockdown causes severe neurodevelopmental defects and Rett-like phenotype with areflexia
PMID: 31692205
3
NTNG2 functions through CaMKII signaling pathways and mutations impair synaptic transmission
PMID: 39151821
4
Homozygous NTNG2 frameshift variants cause developmental delay, hypotonia, and autistic features
PMID: 31372774
5
Reduced NTNG2 mRNA expression found in temporal lobe of schizophrenia and bipolar disorder patients
PMID: 17507910
Disease Associationsβ“˜21
neurodevelopmental disorder with behavioral abnormalities, absent speech, and hypotoniaOpen Targets
0.75Strong
Neurodevelopmental disorderOpen Targets
0.39Weak
complex neurodevelopmental disorderOpen Targets
0.37Weak
AreflexiaOpen Targets
0.34Weak
Global developmental delayOpen Targets
0.34Weak
Generalized hypotoniaOpen Targets
0.33Weak
Stereotypical hand wringingOpen Targets
0.33Weak
AchalasiaOpen Targets
0.32Weak
aneurysmOpen Targets
0.28Weak
ocular hypotensionOpen Targets
0.28Weak
Abnormality of the nervous systemOpen Targets
0.27Weak
pyelonephritisOpen Targets
0.23Weak
genetic disorderOpen Targets
0.19Weak
neurodevelopmental disorder with hypotonia, seizures, and absent languageOpen Targets
0.15Weak
infantile spasmsOpen Targets
0.12Weak
intellectual developmental disorder with macrocephaly, seizures, and speech delayOpen Targets
0.12Weak
intellectual disability, autosomal dominant 6Open Targets
0.12Weak
deafnessOpen Targets
0.05Suggestive
benign adult familial myoclonic epilepsyOpen Targets
0.05Suggestive
mathematical abilityOpen Targets
0.04Suggestive
Neurodevelopmental disorder with behavioral abnormalities, absent speech, and hypotoniaUniProt
Pathogenic Variants8
NM_032536.4(NTNG2):c.483G>A (p.Trp161Ter)Pathogenic
Neurodevelopmental disorder with behavioral abnormalities, absent speech, and hypotonia
β˜…β˜†β˜†β˜†2025β†’ Residue 161
NM_032536.4(NTNG2):c.422T>C (p.Phe141Ser)Likely pathogenic
Abnormality of the nervous system
β˜…β˜†β˜†β˜†2021β†’ Residue 141
NM_032536.4(NTNG2):c.599C>T (p.Ser200Leu)Likely pathogenic
Neurodevelopmental disorder|Neurodevelopmental disorder with behavioral abnormalities, absent speech, and hypotonia
β˜†β˜†β˜†β˜†2022β†’ Residue 200
NM_032536.4(NTNG2):c.242G>A (p.Cys81Tyr)Pathogenic
Neurodevelopmental disorder|Neurodevelopmental disorder with behavioral abnormalities, absent speech, and hypotonia
β˜†β˜†β˜†β˜†2019β†’ Residue 81
NM_032536.4(NTNG2):c.319T>G (p.Trp107Gly)Pathogenic
Neurodevelopmental disorder|Neurodevelopmental disorder with behavioral abnormalities, absent speech, and hypotonia
β˜†β˜†β˜†β˜†2019β†’ Residue 107
NM_032536.4(NTNG2):c.1065C>G (p.Cys355Trp)Pathogenic
Neurodevelopmental disorder|Neurodevelopmental disorder with behavioral abnormalities, absent speech, and hypotonia
β˜†β˜†β˜†β˜†2019β†’ Residue 355
NM_032536.4(NTNG2):c.1367G>A (p.Cys456Tyr)Pathogenic
Neurodevelopmental disorder|Neurodevelopmental disorder with behavioral abnormalities, absent speech, and hypotonia
β˜†β˜†β˜†β˜†2019β†’ Residue 456
NM_032536.4(NTNG2):c.376dup (p.Ser126fs)Pathogenic
Stereotypical hand wringing;Areflexia;Generalized hypotonia;Global developmental delay|Neurodevelopmental disorder with behavioral abnormalities, absent speech, and hypotonia
β˜†β˜†β˜†β˜†2019β†’ Residue 126
View on ClinVar β†—
Related Genes
NTNG1Shared pathway86%CDKL5Protein interaction75%LRRC4CProtein interaction72%LRRC4Protein interaction71%LRRC4BProtein interaction58%SLITRK3Shared pathway38%
Tissue Expression6 tissues
Bone Marrow
100%
Brain
6%
Heart
4%
Lung
3%
Liver
0%
Ovary
0%
Gene Interaction Network
Click a node to explore
NTNG2NTNG1CDKL5LRRC4CLRRC4LRRC4BSLITRK3
PROTEIN STRUCTURE
Preparing viewer…
PDB3TBD Β· 1.80 Γ… Β· X-ray
View on RCSB β†—
Constraintβ“˜
LOEUFβ“˜
0.50Moderately Constrained
pLIβ“˜
0.98Intolerant
Observed/Expected LoF0.33 [0.22–0.50]
RankingsWhere NTNG2 stands among ~20K protein-coding genes
  • #12,625of 20,598
    Most Researched27
  • #3,125of 5,498
    Most Pathogenic Variants8
  • #3,013of 17,882
    Most Constrained (LOEUF)0.50 Β· top quartile
Genes detectedNTNG2
Sources retrieved10 papers
Response timeβ€”
πŸ“„ Sources
10β–Ό
1
Autistic-like behavior and cerebellar dysfunction in Bmal1 mutant mice ameliorated by mTORC1 inhibition.
PMID: 35301425
Mol Psychiatry Β· 2023
1.00
2
Netrin-G2 dysfunction causes a Rett-like phenotype with areflexia.
PMID: 31692205
Hum Mutat Β· 2020
0.90
3
Homozygous Missense Variants in NTNG2, Encoding a Presynaptic Netrin-G2 Adhesion Protein, Lead to a Distinct Neurodevelopmental Disorder.
PMID: 31668703
Am J Hum Genet Β· 2019
0.80
4
Decreased mRNA expression of netrin-G1 and netrin-G2 in the temporal lobe in schizophrenia and bipolar disorder.
PMID: 17507910
Neuropsychopharmacology Β· 2008
0.70
5
Compound heterozygous mutations of NTNG2 cause intellectual disability via inhibition of the CaMKII signaling.
PMID: 39151821
J Genet Genomics Β· 2024
0.60