# NM_001321075.3(DLG4):c.1961C>T (p.Ser654Phe)

https://sugi.bio/variant/dlg4-p-ser654phe

## Summary

**DLG4 p.Ser654Phe (c.1961C>T)** is classified **Uncertain significance** in DLG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-02-19). AlphaMissense: likely pathogenic (0.7855); Very rare (popmax 0.00108%, nfe); Associated with DLG4-Related Synaptopathy.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs752934560 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00108%, nfe)

## For patients & families {#patients}

This is a change in the DLG4 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to DLG4-Related Synaptopathy.

*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:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DLG4](https://sugi.bio/atlas/gene/DLG4/) |
| Protein change (HGVS p.) | p.Ser654Phe |
| Coding change (HGVS c.) | c.1961C>T |
| MANE Select transcript | [NM_001321075](https://www.ncbi.nlm.nih.gov/nuccore/NM_001321075) |
| dbSNP | [rs752934560](https://www.ncbi.nlm.nih.gov/snp/rs752934560/) |
| Variant type | single nucleotide variant |
| Location | chr17:7191908-7191908 (GRCh38) |
| ClinVar | [VCV1199223](https://www.ncbi.nlm.nih.gov/clinvar/variation/1199223/) |

**All HGVS expressions:** `NC_000017.10:g.7095227G>A`, `NC_000017.11:g.7191908G>A`, `NG_008391.2:g.33143C>T`, `NG_008391.3:g.33142C>T`, `NM_001128827.4:c.1952C>T`, `NM_001321074.1:c.2081C>T`, `NM_001321075.3:c.1961C>T`, `NM_001321076.3:c.1781C>T`, `NM_001321077.3:c.1781C>T`, `NM_001365.5:c.2090C>T`, `NM_001369566.3:c.1880C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.7855)
- REVEL 0.517 (indeterminate)
- SaProt LLR -14.884 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 11.756, GERP 2.38, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 29.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.58** across the covering region of the MANE Select transcript (7,190,711–7,203,286), spanning 12,575 bp. Chi-square p 1.2e-30. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00108%** (nfe) · FAF95 0.000574% · FAF99 0.000453% · 12/1,115,248 in the highest group · 12/1,333,138 alleles overall — very rare (popmax 0.00108%, nfe).

*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}

**DLG4** population constraint: LOEUF 0.151, pLI 1, missense-Z 4.8436; 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):

- **complex neurodevelopmental disorder** — Definitive (AD)

## Protein context {#protein}

Residue **654** lies in a modified residue (phosphoserine); a UniProt-annotated variant site (in mrd62); the guanylate kinase-like domain.

AlphaFold model confidence (whole protein): pLDDT 78.00, 52% of residues very-high.

**24 experimental structure(s)** (PDB): [1KEF](https://www.rcsb.org/structure/1KEF), [2MES](https://www.rcsb.org/structure/2MES), [3I4W](https://www.rcsb.org/structure/3I4W), [3K82](https://www.rcsb.org/structure/3K82), [3ZRT](https://www.rcsb.org/structure/3ZRT), [5J7J](https://www.rcsb.org/structure/5J7J) — incl. mutant structure 6QJF.

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

*Describes the biological roles of DLG4 (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:** DLG4's established molecular role includes kinase binding. p.Ser654Phe falls in the guanylate kinase-like domain.


### Pathways affected {#pathways}

DLG4 participates in **14 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of Ca-permeable Kainate Receptor](https://reactome.org/content/detail/R-HSA-451308) | curated |
| [LGI-ADAM interactions](https://reactome.org/content/detail/R-HSA-5682910) | curated |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | curated |
| [RHO GTPases activate CIT](https://reactome.org/content/detail/R-HSA-5625900) | curated |
| [Synaptic adhesion-like molecules](https://reactome.org/content/detail/R-HSA-8849932) | curated |
| [Trafficking of AMPA receptors](https://reactome.org/content/detail/R-HSA-399719) | 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 |
| [Signaling by ERBB4](https://reactome.org/content/detail/R-HSA-1236394) | 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.

**Biological process:** protein localization to synapse, establishment of protein localization, protein-containing complex assembly.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-02-19.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-02-19 |

## Associated conditions {#conditions}

[DLG4-Related Synaptopathy](https://sugi.bio/atlas/disease/dlg4-related-synaptopathy/).

**Reported phenotype names (ClinVar):** DLG4-Related Synaptopathy.

## Similar variants {#similar}

Related DLG4 variant pages (same residue, condition, or type): [DLG4 c.1084-1G>T](/variant/dlg4-c-1084-minus-1g-t), [DLG4 c.1478+2T>C](/variant/dlg4-c-1478-plus-2t-c), [DLG4 c.1543+2T>C](/variant/dlg4-c-1543-plus-2t-c), [DLG4 c.1592-1G>A](/variant/dlg4-c-1592-minus-1g-a), [DLG4 c.1693+1G>A](/variant/dlg4-c-1693-plus-1g-a), [DLG4 c.1866+2T>C](/variant/dlg4-c-1866-plus-2t-c), [DLG4 c.210+1G>T](/variant/dlg4-c-210-plus-1g-t), [DLG4 c.211-2A>G](/variant/dlg4-c-211-minus-2a-g).

### 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 1199223). 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.*