# NM_021120.4(DLG3):c.1462dup (p.Ser488fs)

https://sugi.bio/variant/dlg3-p-ser488fs

## Summary

**DLG3 p.Ser488fs (c.1462dup)** is classified **Likely pathogenic** in DLG3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-31). Associated with intellectual disability, X-linked 90.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the DLG3 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to intellectual disability, X-linked 90.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0022690/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DLG3](https://sugi.bio/atlas/gene/DLG3/) |
| Protein change (HGVS p.) | p.Ser488fs |
| Coding change (HGVS c.) | c.1462dup |
| MANE Select transcript | [NM_021120](https://www.ncbi.nlm.nih.gov/nuccore/NM_021120) |
| Variant type | Duplication |
| Location | chrX:70479205-70479206 (GRCh38) |
| ClinVar | [VCV3770158](https://www.ncbi.nlm.nih.gov/clinvar/variation/3770158/) |

**All HGVS expressions:** `NC_000023.10:g.69699056dup`, `NC_000023.11:g.70479206dup`, `NG_015849.2:g.39352dup`, `NM_001166278.2:c.13dup`, `NM_020730.3:c.451dup`, `NM_021120.4:c.1462dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 3.934, GERP 1.85, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 10 of 19**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**DLG3** population constraint: ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **non-syndromic X-linked intellectual disability** — Definitive (XL)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 74.35, 49% of residues very-high.

**3 experimental structure(s)** (PDB): [1UM7](https://www.rcsb.org/structure/1UM7), [2FE5](https://www.rcsb.org/structure/2FE5), [2I1N](https://www.rcsb.org/structure/2I1N).

## What this gene does {#gene-function}

*Describes the biological roles of DLG3 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** DLG3's established molecular role includes kinase binding.


### Pathways affected {#pathways}

DLG3 participates in **10 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of Ca-permeable Kainate Receptor](https://reactome.org/content/detail/R-HSA-451308) | curated |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | curated |
| [Synaptic adhesion-like molecules](https://reactome.org/content/detail/R-HSA-8849932) | curated |
| [Assembly and cell surface presentation of NMDA receptors](https://reactome.org/content/detail/R-HSA-9609736) | electronic |
| [Long-term potentiation](https://reactome.org/content/detail/R-HSA-9620244) | electronic |
| [Negative regulation of NMDA receptor-mediated neuronal transmission](https://reactome.org/content/detail/R-HSA-9617324) | electronic |
| [Neurexins and neuroligins](https://reactome.org/content/detail/R-HSA-6794361) | electronic |
| [NrCAM interactions](https://reactome.org/content/detail/R-HSA-447038) | electronic |
| [Ras activation upon Ca2+ influx through NMDA receptor](https://reactome.org/content/detail/R-HSA-442982) | electronic |
| [Unblocking of NMDA receptors, glutamate binding and activation](https://reactome.org/content/detail/R-HSA-438066) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** kinase binding, phosphatase binding.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-01-31.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-01-31 |

## Associated conditions {#conditions}

[intellectual disability, X-linked 90](https://sugi.bio/atlas/disease/intellectual-disability-x-linked-90/).

**Reported phenotype names (ClinVar):** Intellectual disability, X-linked 90, INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED 90, DLG3-Related X-Linked Nonsyndromic Mental Retardation.

## Similar variants {#similar}

Related DLG3 variant pages (same residue, condition, or type): [DLG3 p.Asn45fs](/variant/dlg3-p-asn45fs), [DLG3 p.Ser339fs](/variant/dlg3-p-ser339fs), [DLG3 p.Tyr39Ter](/variant/dlg3-p-tyr39ter), [DLG3 c.-8dup](/variant/dlg3-c-minus-8dup), [DLG3 p.Thr365fs](/variant/dlg3-p-thr365fs), [DLG3 p.Arg217Ter](/variant/dlg3-p-arg217ter), [DLG3 p.Arg756Ter](/variant/dlg3-p-arg756ter), [DLG3 p.Val459fs](/variant/dlg3-p-val459fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 3770158). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*