# NM_004393.6(DAG1):c.384G>T (p.Val128=)

https://sugi.bio/variant/dag1-p-val128

## Summary

**DAG1 p.Val128= (c.384G>T)** is classified **Benign** in DAG1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-24). Rare (popmax 0.998%, afr); Associated with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9.

**At a glance:** Benign · review: Multiple submitters · rsID rs143829263 · 4 submitters · 2 linked conditions · rare (popmax 0.998%, afr)

## For patients & families {#patients}

This is a change in the DAG1 gene that is classified as benign — not considered disease-causing, submitted by 4 submitters, and is linked to muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Antenatal, Infancy, Neonatal |
| Prevalence | <1 / 1 000 000 (United Kingdom) |
| Diagnostic panels | DAG1 is a diagnostic-grade gene on 14 Genomics England panels |

**Commonly reported features of Walker-Warburg syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Areflexia — Very frequent (99-80%)
- Pachygyria — Very frequent (99-80%)
- Cerebellar hypoplasia — Very frequent (99-80%)
- Muscle weakness — Very frequent (99-80%)
- Specific learning disability — Very frequent (99-80%)
- Lissencephaly — Very frequent (99-80%)
- Aplasia/Hypoplasia involving the skeletal musculature — Very frequent (99-80%)
- Ventriculomegaly — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016134/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DAG1](https://sugi.bio/atlas/gene/DAG1/) |
| Protein change (HGVS p.) | p.Val128= |
| Coding change (HGVS c.) | c.384G>T |
| MANE Select transcript | [NM_004393](https://www.ncbi.nlm.nih.gov/nuccore/NM_004393) |
| dbSNP | [rs143829263](https://www.ncbi.nlm.nih.gov/snp/rs143829263/) |
| Variant type | single nucleotide variant |
| Location | chr3:49530895-49530895 (GRCh38) |
| ClinVar | [VCV257588](https://www.ncbi.nlm.nih.gov/clinvar/variation/257588/) |

**All HGVS expressions:** `LRG_854:g.65764G>T`, `LRG_854t1:c.384G>T`, `LRG_854t2:c.384G>T`, `NC_000003.11:g.49568328G>T`, `NC_000003.12:g.49530895G>T`, `NG_013230.4:g.65764G>T`, `NM_001165928.4:c.384G>T`, `NM_001177634.3:c.384G>T`, `NM_001177635.3:c.384G>T`, `NM_001177636.3:c.384G>T`, `NM_001177637.3:c.384G>T`, `NM_001177638.3:c.384G>T`, `NM_001177639.3:c.384G>T`, `NM_001177640.3:c.384G>T`, `NM_001177641.3:c.384G>T`, `NM_001177642.3:c.384G>T`, `NM_001177643.3:c.384G>T`, `NM_001177644.3:c.384G>T`, `NM_004393.6:c.384G>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.22) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.3, GERP -3.34, phastCons 0.009 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 7.403**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.22**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.22**, donor gain **0.00**.
- Pangolin: Δ**0.21** (gain), gain 0.21 / loss 0.00. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.998%** (afr) · FAF95 0.939% · FAF99 0.915% · 749/75,034 in the highest group · 867/1,614,146 alleles overall — rare (popmax 0.998%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.998% | 100 |
| Remaining individuals (not grpmax-eligible) | 0.0944% | 1,059 |
| Admixed American | 0.085% | 1,177 |
| South Asian | 0.00329% | 30,357 |
| European (non-Finnish) | 0.000424% | 236,004 |

*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}

**DAG1** population constraint: LOEUF 0.298, pLI 1, missense-Z 2.5564. *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):

- **neuromuscular disease caused by qualitative or quantitative defects of alpha-dystroglycan** — Definitive (AR)

## Protein context {#protein}

Residue **128** lies in the 'required for laminin recognition' region; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 68.44, 32% of residues very-high.

**8 experimental structure(s)** (PDB): [1EG4](https://www.rcsb.org/structure/1EG4), [2MK7](https://www.rcsb.org/structure/2MK7), [5GGP](https://www.rcsb.org/structure/5GGP), [5LLK](https://www.rcsb.org/structure/5LLK), [6JJY](https://www.rcsb.org/structure/6JJY), [7E9K](https://www.rcsb.org/structure/7E9K).

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

*Describes the biological roles of DAG1 (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:** DAG1's established molecular role includes virus receptor activity. p.Val128= falls in the required for laminin recognition region. In Reactome, DAG1 is annotated in disease pathway(s) including **Defective POMGNT1 causes MDDGA3, MDDGB3 and MDDGC3**, **Defective POMT1 causes MDDGA1, MDDGB1 and MDDGC1**.

**Disease mechanism (Reactome):** DAG1 loss or alteration is curated in [Defective POMGNT1 causes MDDGA3, MDDGB3 and MDDGC3](https://reactome.org/content/detail/R-HSA-5083628), [Defective POMT1 causes MDDGA1, MDDGB1 and MDDGC1](https://reactome.org/content/detail/R-HSA-5083633), [Defective POMT2 causes MDDGA2, MDDGB2 and MDDGC2](https://reactome.org/content/detail/R-HSA-5083629).

### Pathways affected {#pathways}

DAG1 participates in **12 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective POMGNT1 causes MDDGA3, MDDGB3 and MDDGC3](https://reactome.org/content/detail/R-HSA-5083628) | curated |
| ⚕ [Defective POMT1 causes MDDGA1, MDDGB1 and MDDGC1](https://reactome.org/content/detail/R-HSA-5083633) | curated |
| ⚕ [Defective POMT2 causes MDDGA2, MDDGB2 and MDDGC2](https://reactome.org/content/detail/R-HSA-5083629) | curated |
| [DAG1 core M1 glycosylations](https://reactome.org/content/detail/R-HSA-8932506) | curated |
| [DAG1 core M2 glycosylations](https://reactome.org/content/detail/R-HSA-8932504) | curated |
| [DAG1 core M3 glycosylations](https://reactome.org/content/detail/R-HSA-8932505) | curated |
| [Matriglycan biosynthesis on DAG1](https://reactome.org/content/detail/R-HSA-9939291) | curated |
| [Regulation of expression of SLITs and ROBOs](https://reactome.org/content/detail/R-HSA-9010553) | curated |
| [ECM proteoglycans](https://reactome.org/content/detail/R-HSA-3000178) | electronic |
| [EGR2 and SOX10-mediated initiation of Schwann cell myelination](https://reactome.org/content/detail/R-HSA-9619665) | electronic |
| [Formation of the dystrophin-glycoprotein complex (DGC)](https://reactome.org/content/detail/R-HSA-9913351) | electronic |
| [Non-integrin membrane-ECM interactions](https://reactome.org/content/detail/R-HSA-3000171) | electronic |

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

**Molecular function:** virus receptor activity, actin binding, serine-type endopeptidase activity, structural constituent of muscle, tubulin binding, vinculin binding.

**Biological process:** membrane protein ectodomain proteolysis, negative regulation of cell migration, microtubule anchoring, negative regulation of MAPK cascade, negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction, basement membrane organization.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-24.

**Submitter consensus:** unanimous (4/4 Benign).

**Submission history:** 4 submissions (2017–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2019-07-03 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-24 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2017-12-13 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2018-05-25 |

## Associated conditions {#conditions}

[muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9](https://sugi.bio/atlas/disease/muscular-dystrophy-dystroglycanopathy-congenital-with-brain-and-eye-anomalies-type-a9/), [autosomal recessive limb-girdle muscular dystrophy type 2P](https://sugi.bio/atlas/disease/autosomal-recessive-limb-girdle-muscular-dystrophy-type-2p/).

**Reported phenotype names (ClinVar):** Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9, not specified, Autosomal recessive limb-girdle muscular dystrophy type 2P, DAG1-related disorder, DAG1-related condition, Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 9, WALKER-WARBURG SYNDROME OR MUSCLE-EYE BRAIN DISEASE, DAG1-RELATED, Limb-Girdle Muscular Dystrophy Type 9C, MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 2P, MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY, LIMB-GIRDLE, DAG1-RELATED.

## Similar variants {#similar}

Related DAG1 variant pages (same residue, condition, or type): [DAG1 p.Ser14Ter](/variant/dag1-p-ser14ter), [DAG1 p.Trp110Ter](/variant/dag1-p-trp110ter), [DAG1 p.Ala135Ser](/variant/dag1-p-ala135ser), [DAG1 p.Ala135Thr](/variant/dag1-p-ala135thr), [DAG1 p.Ala279Ser](/variant/dag1-p-ala279ser), [DAG1 p.Ala285Thr](/variant/dag1-p-ala285thr), [DAG1 p.Ala285Val](/variant/dag1-p-ala285val), [DAG1 p.Ala610Val](/variant/dag1-p-ala610val).

### 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 257588). 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.*