# NM_018972.4(GDAP1):c.102= (p.Ser34=)

https://sugi.bio/variant/gdap1-p-ser34

## Summary

**GDAP1 p.Ser34= (c.102=)** is classified **Benign/Likely benign** in GDAP1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease type 4A.

**At a glance:** Benign/Likely benign · review: Multiple submitters · 5 submitters · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the GDAP1 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 5 submitters, and is linked to Charcot-Marie-Tooth disease type 4A.

*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) | Infancy, Neonatal |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | GDAP1 is a diagnostic-grade gene on 10 Genomics England panels |

**Commonly reported features of Charcot-Marie-Tooth disease type 4A** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Decreased nerve conduction velocity — Very frequent (99-80%)
- Abnormal foot morphology — Very frequent (99-80%)
- Pes cavus — Very frequent (99-80%)
- Distal muscle weakness — Very frequent (99-80%)
- Distal sensory impairment — Very frequent (99-80%)
- EMG abnormality — Very frequent (99-80%)
- Distal amyotrophy — Very frequent (99-80%)
- Poor fine motor coordination — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0001252/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.Ser34= |
| Coding change (HGVS c.) | c.102= |
| MANE Select transcript | [NM_018972](https://www.ncbi.nlm.nih.gov/nuccore/NM_018972) |
| Variant type | Variation |
| Location | chr8:74350563-74350563 (GRCh38) |
| ClinVar | [VCV695131](https://www.ncbi.nlm.nih.gov/clinvar/variation/695131/) |

**All HGVS expressions:** `LRG_244:g.34434=`, `LRG_244t1:c.102=`, `NC_000008.10:g.75262798G>C`, `NC_000008.11:g.74350563=`, `NG_008787.3:g.34434=`, `NM_001040875.4:c.-64+91=`, `NM_001362929.2:c.-81=`, `NM_001362930.2:c.102=`, `NM_001362931.2:c.102=`, `NM_001362932.2:c.-33=`, `NM_018972.4:c.102=`

## 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 1.09, GERP -0.488, phastCons 1 — weakly conserved position
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for GDAP1 (377 scored positions, the nearest 3 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **34** lies in the gst n-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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** conflicting (4 Benign, 1 Likely benign).

**Submission history:** 5 submissions (2024–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Clinical Genetics, Academic Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Benign | no assertion criteria provided | clinical testing |  |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-27 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Charcot-Marie-Tooth disease type 4A, not specified, not provided, AllHighlyPenetrant, Charcot-Marie-Tooth disease, demyelinating, autosomal recessive, type 4a, none provided.

## Similar variants {#similar}

Related GDAP1 variant pages (same residue, condition, or type): [GDAP1 p.Ser34fs](/variant/gdap1-p-ser34fs), [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), [GDAP1 p.Arg191Ter](/variant/gdap1-p-arg191ter).

### 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 695131). 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.*