# NM_014750.5(DLGAP5):c.235C>T (p.Pro79Ser)

https://sugi.bio/variant/dlgap5-p-pro79ser

## Summary

**DLGAP5 p.Pro79Ser (c.235C>T)** is classified **Uncertain significance** in DLGAP5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-13). AlphaMissense: likely benign (0.088); Very rare (popmax 0.000509%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.000509%, nfe)

## For patients & families {#patients}

This is a change in the DLGAP5 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [DLGAP5](https://sugi.bio/atlas/gene/DLGAP5/) |
| Protein change (HGVS p.) | p.Pro79Ser |
| Coding change (HGVS c.) | c.235C>T |
| MANE Select transcript | [NM_014750](https://www.ncbi.nlm.nih.gov/nuccore/NM_014750) |
| Variant type | single nucleotide variant |
| Location | chr14:55188945-55188945 (GRCh38) |
| ClinVar | [VCV4012107](https://www.ncbi.nlm.nih.gov/clinvar/variation/4012107/) |

**All HGVS expressions:** `NC_000014.8:g.55655663G>A`, `NC_000014.9:g.55188945G>A`, `NM_001146015.2:c.235C>T`, `NM_014750.5:c.235C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.088)
- REVEL 0.039 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.507 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 1.191, GERP -4.3, phastCons 0.999 — weakly conserved position
- CADD: **PHRED 14.12**. 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 1.05** across the covering region of the MANE Select transcript (55,148,354–55,189,179), spanning 40,825 bp. Chi-square p 0.094. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.49 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000509%** (nfe) · FAF95 0.000183% · FAF99 0.00012% · 6/1,178,226 in the highest group · 6/1,610,752 alleles overall — very rare (popmax 0.000509%, 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}

**DLGAP5** population constraint: LOEUF 1.112, pLI 4.2927e-23, missense-Z -0.19594. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 56.52, 18% of residues very-high.

**4 experimental structure(s)** (PDB): [7ZX4](https://www.rcsb.org/structure/7ZX4), [8X9P](https://www.rcsb.org/structure/8X9P), [9DHZ](https://www.rcsb.org/structure/9DHZ), [9DUQ](https://www.rcsb.org/structure/9DUQ).

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

*Describes the biological roles of DLGAP5 (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.*


### Pathways affected {#pathways}

DLGAP5 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [NOTCH3 Intracellular Domain Regulates Transcription](https://reactome.org/content/detail/R-HSA-9013508) | curated |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-05-13.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-05-13 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related DLGAP5 variant pages (same residue, condition, or type): [DLG1 p.His120Arg](/variant/dlg1-p-his120arg), [DLG1 p.Ala262=](/variant/dlg1-p-ala262), [DLG1 p.Asp633Glu](/variant/dlg1-p-asp633glu), [DLG1 p.Ser470=](/variant/dlg1-p-ser470), [DLG1 p.Val167=](/variant/dlg1-p-val167), [DLGAP5 c.1049+7A>C](/variant/dlgap5-c-1049-plus-7a-c), [DLGAP5 c.2064-1G>A](/variant/dlgap5-c-2064-minus-1g-a), [DLG1 c.484-11849C>T](/variant/dlg1-c-484-minus-11849c-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 4012107). 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.*