# NM_018972.4(GDAP1):c.458C>T (p.Pro153Leu)

https://sugi.bio/variant/gdap1-p-pro153leu

## Summary

**GDAP1 p.Pro153Leu (c.458C>T)** is classified **Pathogenic/Likely pathogenic** in GDAP1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-11-07). AlphaMissense: likely pathogenic (0.9905); Very rare (popmax 0.005%, amr); Associated with GDAP1-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs538412810 · 9 submitters · 7 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.005%, amr)

## For patients & families {#patients}

This is a change in the GDAP1 gene that is considered likely disease-causing, submitted by 9 submitters, and is linked to GDAP1-related disorder.

*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.*

**Support & next steps:** [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.Pro153Leu |
| Coding change (HGVS c.) | c.458C>T |
| MANE Select transcript | [NM_018972](https://www.ncbi.nlm.nih.gov/nuccore/NM_018972) |
| dbSNP | [rs538412810](https://www.ncbi.nlm.nih.gov/snp/rs538412810/) |
| Variant type | single nucleotide variant |
| Location | chr8:74360284-74360284 (GRCh38) |
| ClinVar | [VCV406135](https://www.ncbi.nlm.nih.gov/clinvar/variation/406135/) |

**All HGVS expressions:** `LRG_244:g.44155C>T`, `LRG_244t1:c.458C>T`, `NC_000008.10:g.75272519C>T`, `NC_000008.11:g.74360284C>T`, `NG_008787.3:g.44155C>T`, `NM_001040875.4:c.254C>T`, `NM_001362929.2:c.131C>T`, `NM_001362930.2:c.311-1600C>T`, `NM_001362931.2:c.458C>T`, `NM_001362932.2:c.131C>T`, `NM_018972.4:c.458C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9905) — concordant with the pathogenic call
- REVEL 0.902 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.746 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.69, GERP 2.15, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 8%** most-pathogenic-predicted substitutions in GDAP1 (of 2,090 modeled).
- CADD: **PHRED 32.0**. 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 0.86** across the covering region of the MANE Select transcript (74,350,462–74,364,364), spanning 13,902 bp. Chi-square p 0.0041. 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 **0.005%** (amr) · FAF95 0.00133% · FAF99 0.000668% · 3/60,008 in the highest group · 16/1,613,894 alleles overall — very rare (popmax 0.005%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.005% | 20,003 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,602 |
| South Asian | 0.00329% | 30,357 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,250 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,028 |
| European (non-Finnish) | 0.000509% | 196,637 |

*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 **153** 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 2025-11-07.

**Submitter consensus:** conflicting (4 Pathogenic, 3 Likely pathogenic, 2 Uncertain significance).

**Submission history:** 9 submissions (2016–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Inherited Neuropathy Consortium | Uncertain significance | no assertion criteria provided | literature only |  |
| CMT Laboratory, Bogazici University | Pathogenic | criteria provided, single submitter | clinical testing | 2020-12-01 |
| Kariminejad - Najmabadi Pathology & Genetics Center | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-07-10 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-09-30 |
| Inherited Neuropathy Consortium Ii, University Of Miami | Uncertain significance | no assertion criteria provided | literature only | 2016-01-06 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-11-07 |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-11-15 |
| First Genomix Gene Laboratory, Genetic Diagnostics Department | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-17 |
| 3billion | Pathogenic | criteria provided, single submitter | clinical testing | 2025-10-30 |

## Associated conditions {#conditions}

[GDAP1-related disorder](https://sugi.bio/atlas/disease/gdap1-related-disorder/), [peripheral neuropathy](https://sugi.bio/atlas/disease/peripheral-neuropathy/), [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 axonal type 2K](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-axonal-type-2k/), [Charcot-Marie-Tooth disease recessive intermediate A](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-recessive-intermediate-a/), [Charcot-Marie-Tooth disease](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease/).

**Reported phenotype names (ClinVar):** GDAP1-related disorder, Charcot-Marie-Tooth disease type 4A, Charcot-Marie-Tooth disease, Peripheral neuropathy, Charcot-Marie-Tooth disease axonal type 2K, Charcot-Marie-Tooth disease recessive intermediate A, Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive, not provided, GDAP1-related condition, GDAP1-related disorders.

## Same-residue context {#hotspot}

Residue **153** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [GDAP1 p.Pro153Ser](/variant/gdap1-p-pro153ser). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related GDAP1 variant pages (same residue, condition, or type): [GDAP1 p.Pro153Ser](/variant/gdap1-p-pro153ser), [GDAP1 p.Pro153=](/variant/gdap1-p-pro153), [GDAP1 p.Pro153Gln](/variant/gdap1-p-pro153gln), [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).

### 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 406135). 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.*