# NM_018972.4(GDAP1):c.693A>T (p.Pro231=)

https://sugi.bio/variant/gdap1-p-pro231

## Summary

**GDAP1 p.Pro231= (c.693A>T)** is classified **Conflicting classifications of pathogenicity** in GDAP1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-02-01). Ultra-rare (popmax 0.0195%, nfe); Associated with Charcot-Marie-Tooth disease.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs181157785 · 6 submitters · 4 linked conditions · ultra-rare (popmax 0.0195%, nfe)

## For patients & families {#patients}

This is a change in the GDAP1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 6 submitters, and is linked to Charcot-Marie-Tooth disease.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 59 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006034/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.Pro231= |
| Coding change (HGVS c.) | c.693A>T |
| MANE Select transcript | [NM_018972](https://www.ncbi.nlm.nih.gov/nuccore/NM_018972) |
| dbSNP | [rs181157785](https://www.ncbi.nlm.nih.gov/snp/rs181157785/) |
| Variant type | single nucleotide variant |
| Location | chr8:74363052-74363052 (GRCh38) |
| ClinVar | [VCV379724](https://www.ncbi.nlm.nih.gov/clinvar/variation/379724/) |

**All HGVS expressions:** `LRG_244:g.46923A>T`, `LRG_244t1:c.693A>T`, `NC_000008.10:g.75275287A>T`, `NC_000008.11:g.74363052A>T`, `NG_008787.3:g.46923A>T`, `NM_001040875.4:c.489A>T`, `NM_001362929.2:c.366A>T`, `NM_001362930.2:c.519A>T`, `NM_001362931.2:c.693A>T`, `NM_001362932.2:c.366A>T`, `NM_018972.4:c.693A>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 (below), not from a missing predictor score.
- Conservation: phyloP 2.141, GERP -3.76, phastCons 0.999 — highly conserved position (PP3-type support)
- CADD: **PHRED 14.23**. 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: **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 **0.0195%** (nfe) · FAF95 0.0171% · FAF99 0.0161% · 176/904,836 in the highest group · 181/1,312,646 alleles overall — ultra-rare (popmax 0.0195%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0195% | 5,141 |
| Remaining individuals (not grpmax-eligible) | 0.00571% | 17,513 |
| Admixed American | 0.00336% | 29,802 |

*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 **231** 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-02-01.

**Submitter consensus:** conflicting (4 Uncertain significance, 2 Likely benign).

**Submission history:** 7 submissions (2015–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Molecular Genetics Laboratory, London Health Sciences Centre | Likely benign | criteria provided, single submitter | clinical testing |  |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2015-05-27 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-02-01 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-11-16 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Charcot-Marie-Tooth disease, not specified, Charcot-Marie-Tooth disease type 4A, Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive, Charcot-Marie-Tooth disease recessive intermediate A, Lung cancer, not provided, none provided, Charcot-Marie-Tooth Neuropathy, Charcot-Marie-Tooth Hereditary Neuropathy.

## Same-residue context {#hotspot}

Residue **231** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [GDAP1 p.Pro231Leu](/variant/gdap1-p-pro231leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related GDAP1 variant pages (same residue, condition, or type): [GDAP1 p.Pro231Leu](/variant/gdap1-p-pro231leu), [GDAP1 p.Pro231Ser](/variant/gdap1-p-pro231ser), [GDAP1 c.311-1G>A](/variant/gdap1-c-311-minus-1g-a), [GDAP1 c.579+1G>A](/variant/gdap1-c-579-plus-1g-a), [GDAP1 c.694+1G>A](/variant/gdap1-c-694-plus-1g-a), [GDAP1 p.Arg120Trp](/variant/gdap1-p-arg120trp), [GDAP1 p.Arg125Ter](/variant/gdap1-p-arg125ter), [GDAP1 p.Arg161His](/variant/gdap1-p-arg161his).

### 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 379724). 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.*