# NM_177433.3(MAGED2):c.386_387del (p.Val129fs)

https://sugi.bio/variant/maged2-p-val129fs

## Summary

**MAGED2 p.Val129fs (c.386_387del)** is classified **Pathogenic** in MAGED2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2016-09-23). No gnomAD frequency available for this variant; Associated with Bartter disease type 5.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs878854406 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the MAGED2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Bartter disease type 5.

*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 dominant, Autosomal recessive, X-linked recessive |
| Age of onset (of this condition) | Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Diagnostic panels | MAGED2 is a diagnostic-grade gene on 3 Genomics England panels |

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

- Abnormality of metabolism/homeostasis — Very frequent (99-80%)
- Short stature — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0022308/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MAGED2](https://sugi.bio/atlas/gene/MAGED2/) |
| Protein change (HGVS p.) | p.Val129fs |
| Coding change (HGVS c.) | c.386_387del |
| MANE Select transcript | [NM_177433](https://www.ncbi.nlm.nih.gov/nuccore/NM_177433) |
| dbSNP | [rs878854406](https://www.ncbi.nlm.nih.gov/snp/rs878854406/) |
| Variant type | Microsatellite |
| Location | chrX:54810060-54810061 (GRCh38) |
| ClinVar | [VCV226033](https://www.ncbi.nlm.nih.gov/clinvar/variation/226033/) |

**All HGVS expressions:** `NC_000023.10:g.54836493TG[1]`, `NC_000023.11:g.54810060TG[1]`, `NG_012844.1:g.7323TG[1]`, `NM_014599.6:c.386_387del`, `NM_177433.3:c.386_387del`, `NM_201222.3:c.386_387del`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP 0.113, GERP -2.96, phastCons 0.069 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 13**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}


Curated gene–disease validity (ClinGen):

- **Bartter disease type 5** — Definitive (XL)

## Protein context {#protein}

Residue **129** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 59.89, 16% of residues very-high.

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

*Describes the biological roles of MAGED2 (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}

MAGED2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | curated |

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

**Biological process:** female pregnancy, renal sodium ion absorption.

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2016-09-23.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2016-09-23 |

## Associated conditions {#conditions}

[Bartter disease type 5](https://sugi.bio/atlas/disease/bartter-disease-type-5/).

**Reported phenotype names (ClinVar):** Bartter disease type 5, Bartter syndrome, type 5, antenatal, transient.

## Similar variants {#similar}

Related MAGED2 variant pages (same residue, condition, or type): [MAGED2 p.486AAEA[1]](/variant/maged2-p-486aaea-1), [MAGED2 c.1271+4_1271+7del](/variant/maged2-c-1271-plus-4-1271-plus-7del), [MAGED2 p.Pro153Ser](/variant/maged2-p-pro153ser), [MAGED2 p.Ala208=](/variant/maged2-p-ala208), [MAGED2 p.Pro272=](/variant/maged2-p-pro272), [MAGED2 p.Ser327=](/variant/maged2-p-ser327), [MAGED2 p.Ser84=](/variant/maged2-p-ser84), [MAGED2 p.Thr132=](/variant/maged2-p-thr132).

### 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 226033). 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.*