# NM_018972.4(GDAP1):c.786del (p.Phe263fs)

https://sugi.bio/variant/gdap1-p-phe263fs

## Summary

**GDAP1 p.Phe263fs (c.786del)** is classified **Pathogenic/Likely pathogenic** in GDAP1 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2025-05-28). No gnomAD frequency available for this variant; Associated with Charcot-Marie-Tooth disease recessive intermediate A.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1060500978 · 11 submitters · 3 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the GDAP1 gene that is considered likely disease-causing, submitted by 11 submitters, and is linked to Charcot-Marie-Tooth disease recessive intermediate A.

*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 |
| Diagnostic panels | GDAP1 is a diagnostic-grade gene on 10 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012453/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GDAP1](https://sugi.bio/atlas/gene/GDAP1/) |
| Protein change (HGVS p.) | p.Phe263fs |
| Coding change (HGVS c.) | c.786del |
| MANE Select transcript | [NM_018972](https://www.ncbi.nlm.nih.gov/nuccore/NM_018972) |
| dbSNP | [rs1060500978](https://www.ncbi.nlm.nih.gov/snp/rs1060500978/) |
| Variant type | Deletion |
| Location | chr8:74364073-74364073 (GRCh38) |
| ClinVar | [VCV406136](https://www.ncbi.nlm.nih.gov/clinvar/variation/406136/) |

**All HGVS expressions:** `LRG_244:g.47947del`, `LRG_244t1:c.786del`, `NC_000008.10:g.75276311del`, `NC_000008.11:g.74364076del`, `NG_008787.3:g.47947del`, `NM_001040875.4:c.582del`, `NM_001362929.2:c.459del`, `NM_001362930.2:c.612del`, `NM_001362931.2:c.694+1023del`, `NM_001362932.2:c.459del`, `NM_018972.2:c.786_786delG`, `NM_018972.4:c.786del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 7.871, GERP 2.77, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.963, pLI 0.00023132. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (6 of 6)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion 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}

**GDAP1** population constraint: LOEUF 0.963, pLI 0.00023132, missense-Z 1.171. *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):

- **Charcot-Marie-Tooth disease** — Definitive (SD)

## Protein context {#protein}

Residue **263** lies in the gst c-terminal domain.

AlphaFold model confidence (whole protein): pLDDT 87.68, 69% of residues very-high.

**8 experimental structure(s)** (PDB): [7AIA](https://www.rcsb.org/structure/7AIA), [7ALM](https://www.rcsb.org/structure/7ALM), [7B2G](https://www.rcsb.org/structure/7B2G), [7Q6J](https://www.rcsb.org/structure/7Q6J), [7Q6K](https://www.rcsb.org/structure/7Q6K), [7YWD](https://www.rcsb.org/structure/7YWD) — incl. mutant structure 7B2G.

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

*Describes the biological roles of GDAP1 (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}

GDAP1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Class I peroxisomal membrane protein import](https://reactome.org/content/detail/R-HSA-9603798) | curated |

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

**Biological process:** mitochondrial fission, obsolete protein targeting to mitochondrion, mitochondrial fusion.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-05-28.

**Submitter consensus:** conflicting (7 Pathogenic, 3 Uncertain significance, 1 Likely pathogenic).

**Submission history:** 11 submissions (2016–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2018-08-23 |
| Inherited Neuropathy Consortium | Uncertain significance | no assertion criteria provided | literature only |  |
| Genesis Genome Database | Uncertain significance | no assertion criteria provided | research | 2019-08-14 |
| CMT Laboratory, Bogazici University | Pathogenic | criteria provided, single submitter | clinical testing | 2020-12-01 |
| 3billion | Pathogenic | criteria provided, single submitter | clinical testing | 2022-01-03 |
| Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Pathogenic | criteria provided, single submitter | curation | 2023-05-02 |
| Inherited Neuropathy Consortium Ii, University Of Miami | Uncertain significance | no assertion criteria provided | literature only | 2016-01-06 |
| MGZ Medical Genetics Center | Pathogenic | criteria provided, single submitter | clinical testing | 2021-10-21 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-01-06 |
| Variantyx, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2025-05-28 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2017-08-01 |

## Associated conditions {#conditions}

[Charcot-Marie-Tooth disease recessive intermediate A](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-recessive-intermediate-a/), [Charcot-Marie-Tooth disease type 4A](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-type-4a/), [Charcot-Marie-Tooth disease](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease/).

**Reported phenotype names (ClinVar):** Charcot-Marie-Tooth disease recessive intermediate A, Charcot-Marie-Tooth disease type 4A, not provided, Charcot-Marie-Tooth disease, Charcot-Marie-Tooth Neuropathy, Charcot-Marie-Tooth Hereditary Neuropathy, none provided, CHARCOT-MARIE-TOOTH NEUROPATHY, RECESSIVE INTERMEDIATE A, Charcot-Marie-Tooth disease, demyelinating, autosomal recessive, type 4a.

## Similar variants {#similar}

Related GDAP1 variant pages (same residue, condition, or type): [GDAP1 p.Glu168fs](/variant/gdap1-p-glu168fs), [GDAP1 p.Met1fs](/variant/gdap1-p-met1fs), [GDAP1 p.Pro179fs](/variant/gdap1-p-pro179fs), [GDAP1 p.Tyr279_Tyr280insTer](/variant/gdap1-p-tyr279-tyr280inster), [GDAP1 c.311-1790_408del](/variant/gdap1-c-311-minus-1790-408del), [GDAP1 c.485-2del](/variant/gdap1-c-485-minus-2del), [GDAP1 p.Ala184fs](/variant/gdap1-p-ala184fs), [GDAP1 p.Ala312fs](/variant/gdap1-p-ala312fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 406136). 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.*