# NM_004393.6(DAG1):c.5G>C (p.Arg2Thr)

https://sugi.bio/variant/dag1-p-arg2thr

## Summary

**DAG1 p.Arg2Thr (c.5G>C)** is classified **Uncertain significance** in DAG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-19). AlphaMissense: likely benign (0.0976); Very rare (popmax 8.47e-05%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy type 2P.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs781269339 · 1 submitter · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the DAG1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to autosomal recessive limb-girdle muscular dystrophy type 2P.

*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) | Childhood |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | DAG1 is a diagnostic-grade gene on 14 Genomics England panels |

**Commonly reported features of Alpha-dystroglycan-related limb-girdle muscular dystrophy R16** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Elevated circulating creatine kinase concentration — Very frequent (99-80%)
- Limb-girdle muscular dystrophy — Very frequent (99-80%)
- Reduced muscle fiber alpha dystroglycan — Very frequent (99-80%)
- Motor delay — Frequent (79-30%)
- Unsteady gait — Frequent (79-30%)
- Waddling gait — Frequent (79-30%)
- Difficulty climbing stairs — Frequent (79-30%)
- Calf muscle hypertrophy — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012541/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.Arg2Thr |
| Coding change (HGVS c.) | c.5G>C |
| MANE Select transcript | [NM_004393](https://www.ncbi.nlm.nih.gov/nuccore/NM_004393) |
| dbSNP | [rs781269339](https://www.ncbi.nlm.nih.gov/snp/rs781269339/) |
| Variant type | single nucleotide variant |
| Location | chr3:49510539-49510539 (GRCh38) |
| ClinVar | [VCV2114707](https://www.ncbi.nlm.nih.gov/clinvar/variation/2114707/) |

**All HGVS expressions:** `LRG_854:g.45408G>C`, `LRG_854t1:c.5G>C`, `LRG_854t2:c.5G>C`, `NC_000003.11:g.49547972G>C`, `NC_000003.12:g.49510539G>C`, `NG_013230.4:g.45408G>C`, `NM_001165928.4:c.5G>C`, `NM_001177634.3:c.5G>C`, `NM_001177635.3:c.5G>C`, `NM_001177636.3:c.5G>C`, `NM_001177637.3:c.5G>C`, `NM_001177638.3:c.5G>C`, `NM_001177639.3:c.5G>C`, `NM_001177640.3:c.5G>C`, `NM_001177641.3:c.5G>C`, `NM_001177642.3:c.5G>C`, `NM_001177643.3:c.5G>C`, `NM_001177644.3:c.5G>C`, `NM_004393.6:c.5G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0976)
- REVEL 0.075 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.086 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 5.798, GERP -0.301, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 21.9**. 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 0.82** across the covering region of the MANE Select transcript (49,510,535–49,531,082), spanning 20,547 bp. Chi-square p 0.0053. 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 **8.47e-05%** (nfe) · 1/1,180,004 in the highest group · 2/1,613,060 alleles overall — very rare (popmax 8.47e-05%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,418 |
| European (non-Finnish) (grpmax) | 8.47e-05% | 1,180,004 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}


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. 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-03-19.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-03-19 |

## Associated conditions {#conditions}

[autosomal recessive limb-girdle muscular dystrophy type 2P](https://sugi.bio/atlas/disease/autosomal-recessive-limb-girdle-muscular-dystrophy-type-2p/), [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/).

**Reported phenotype names (ClinVar):** Autosomal recessive limb-girdle muscular dystrophy type 2P, Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9, MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 2P, Limb-Girdle Muscular Dystrophy Type 9C, MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY, LIMB-GIRDLE, DAG1-RELATED, WALKER-WARBURG SYNDROME OR MUSCLE-EYE BRAIN DISEASE, DAG1-RELATED, Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 9.

## Similar variants {#similar}

Related DAG1 variant pages (same residue, condition, or type): [DAG1 p.Arg2Lys](/variant/dag1-p-arg2lys), [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).

### 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 2114707). 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.*