DLG4-Related Synaptopathy: genes and variants
Explore variant evidence for DLG4-Related Synaptopathy across 3 analyzed proteins (DLG4, GRIA1, SETD2). Linked ClinVar records include 12 pathogenic or likely pathogenic variants, 36 variants of uncertain significance and 7 with conflicting classifications.
Coverage includes proteins already analyzed in CATVariant, not every gene involved in this condition. Database links are associations, not an assessment of clinical gene–disease validity. Computable evidence prioritizes variants for expert review and does not reclassify them. Source labels are pooled across this disease family.
Data updated 2026-10-10. Automated aggregation, not a clinical review date.
Download variant evidence (CSV)
Genes linked to DLG4-Related Synaptopathy
DLG4: Disks large homolog 4
It organizes glutamate receptors, signaling enzymes, and cytoskeletal proteins at excitatory postsynaptic densities, making it central to synaptic transmission and plasticity. Haploinsufficiency can cause a neurodevelopmental disorder with intellectual disability, autism-related features, and sometimes epilepsy.
6 ClinVar pathogenic / likely pathogenic and 20 uncertain variants in DLG4 have source records linked to DLG4-Related Synaptopathy. Association strength is not clinical gene validity.
GRIA1: Glutamate receptor 1
An AMPA-type glutamate receptor subunit that forms a ligand-gated cation channel at excitatory synapses. Glutamate opens the receptor to convert a chemical signal into an electrical response, supporting fast transmission and activity-dependent plasticity in the brain.
5 ClinVar pathogenic / likely pathogenic and 9 uncertain variants in GRIA1 have source records linked to DLG4-Related Synaptopathy. Association strength is not clinical gene validity.
SETD2: Histone-lysine N-methyltransferase SETD2
It deposits H3K36 trimethylation across actively transcribed genes and helps coordinate RNA processing, DNA repair, and genome stability. Somatic loss is common in renal and other cancers, while germline pathogenic variants can cause Luscan-Lumish overgrowth syndrome.
1 ClinVar pathogenic / likely pathogenic and 12 uncertain variants in SETD2 have source records linked to DLG4-Related Synaptopathy. Association strength is not clinical gene validity.
Weakly linked (only a few uncertain records): OCRL and SPTA1.
Where DLG4-Related Synaptopathy variants cluster
- DLG4 Guanylate kinase-like (positions 534–709): 4 of 6 ClinVar pathogenic / likely pathogenic variants, 2.7× more than its size predicts.
ClinVar pathogenic and likely pathogenic variants linked to DLG4-Related Synaptopathy
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| DLG4 D186V | 186 | PDZ 2 | Pathogenic / likely pathogenic (★★) |
| DLG4 R586Q | 586 | Guanylate kinase-like | Pathogenic / likely pathogenic (★★) |
| DLG4 T611I | 611 | Guanylate kinase-like | Pathogenic / likely pathogenic (★★) |
| DLG4 G177V | 177 | PDZ 2 | Pathogenic / likely pathogenic (★★) |
| GRIA1 A636T | 636 | Extracellular | Pathogenic / likely pathogenic (★★) |
| DLG4 P564S | 564 | Guanylate kinase-like | Pathogenic / likely pathogenic (★) |
| GRIA1 P508Q | 508 | Extracellular | Pathogenic / likely pathogenic (★) |
| GRIA1 G513E | 513 | Extracellular | Pathogenic / likely pathogenic (★) |
| GRIA1 S872T | 872 | Cytoplasmic | Pathogenic / likely pathogenic (★) |
| SETD2 V1743L | 1743 | Pathogenic / likely pathogenic (★) | |
| DLG4 P536L | 536 | Guanylate kinase-like | Pathogenic / likely pathogenic |
| GRIA1 G745D | 745 | Extracellular | Pathogenic / likely pathogenic |
Which prediction tools work for DLG4-Related Synaptopathy
Observed separation of ClinVar pathogenic / likely pathogenic from benign / likely benign variants (AUROC × 100). This benchmark is not a clinical recommendation.
- PolyPhen-2: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
Same protein, different disease
- Luscan-Lumish syndrome also has ClinVar records linked to SETD2 variants; they fall mostly in different places as the DLG4-Related Synaptopathy variants (5 pathogenic / likely pathogenic).
Diseases related to DLG4-Related Synaptopathy
- Epilepsy, also linked to GRIA1
- Luscan-Lumish syndrome, also linked to SETD2
- Migraine, also linked to GRIA1
- Lennox-Gastaut syndrome, also linked to GRIA1
Frequently asked questions
Which genes have records linked to DLG4-Related Synaptopathy?
This view contains 3 analyzed proteins: DLG4, GRIA1, SETD2. Links come from clinical records and association databases. They do not imply that every listed gene is a validated cause, and missing genes may not yet be analyzed.
What do the clinical classifications mean?
Linked records include 12 pathogenic or likely pathogenic variants, 36 variants of uncertain significance and 7 with conflicting classifications. Labels summarize source records; multi-condition records may not make a separate assertion for this disease. Check the original record and review status.
Does the evidence score change a VUS classification?
No. 0 VUS or conflicting variants reach the likely-pathogenic points range on the computable criteria available here. This is a research prioritization signal, not a clinical classification. Patient, family and other required evidence may be missing.
Can I download the variant evidence?
Download the CSV for all 87 variants in the selected disease scope, including clinical labels, review status, evidence criteria, predictor scores, functional measurements and population frequency where available.
About this data
Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from eligible public CATVariant analyses of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.
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