# NM_018972.4(GDAP1):c.507T>G (p.Ser169=)

https://sugi.bio/variant/gdap1-p-ser169

## Summary

**GDAP1 p.Ser169= (c.507T>G)** is classified **Benign** in GDAP1 (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-02-04). Common (popmax 33%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with Charcot-Marie-Tooth disease recessive intermediate A.

**At a glance:** Benign · review: Multiple submitters · rsID rs11554166 · 13 submitters · 5 linked conditions · common (popmax 33%, nfe) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the GDAP1 gene that is classified as benign — not considered disease-causing, submitted by 13 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.Ser169= |
| Coding change (HGVS c.) | c.507T>G |
| MANE Select transcript | [NM_018972](https://www.ncbi.nlm.nih.gov/nuccore/NM_018972) |
| dbSNP | [rs11554166](https://www.ncbi.nlm.nih.gov/snp/rs11554166/) |
| Variant type | single nucleotide variant |
| Location | chr8:74361906-74361906 (GRCh38) |
| ClinVar | [VCV261065](https://www.ncbi.nlm.nih.gov/clinvar/variation/261065/) |

**All HGVS expressions:** `LRG_244:g.45777T>G`, `LRG_244t1:c.507T>G`, `NC_000008.10:g.75274141T>G`, `NC_000008.11:g.74361906T>G`, `NG_008787.3:g.45777T>G`, `NM_001040875.4:c.303T>G`, `NM_001362929.2:c.180T>G`, `NM_001362930.2:c.333T>G`, `NM_001362931.2:c.507T>G`, `NM_001362932.2:c.180T>G`, `NM_018972.4:c.507T>G`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 33%, nfe) — too common for a highly-penetrant pathogenic allele.

- **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 -0.775, GERP -5.21, phastCons 0.011 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 5.435**. 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 **33%** (nfe) · FAF95 33% · FAF99 32.9% · 383,720/1,161,382 in the highest group · 485,695/1,593,766 alleles overall — common (popmax 33%, nfe) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 33.2% | 3 |
| European (non-Finnish) (grpmax) | 33% | 3 |
| Amish (not grpmax-eligible) | 31.4% | 3 |
| Remaining individuals (not grpmax-eligible) | 29.4% | 3 |
| Ashkenazi Jewish (not grpmax-eligible) | 28.9% | 3 |
| East Asian | 28.2% | 4 |
| Middle Eastern | 26.1% | 4 |
| South Asian | 20.8% | 5 |
| Admixed American | 20.6% | 5 |
| African / African-American | 11.3% | 9 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **169** 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}

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

**Submitter consensus:** conflicting (11 Benign, 2 Uncertain significance, 1 benign).

**Submission history:** 14 submissions (2015–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-27 |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| Molecular Genetics Laboratory, London Health Sciences Centre | Benign | criteria provided, single submitter | clinical testing |  |
| Clinical Genetics, Academic Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Inherited Neuropathy Consortium Ii, University Of Miami | Uncertain significance | no assertion criteria provided | literature only | 2016-01-06 |
| Athena Diagnostics | benign | criteria provided, single submitter | clinical testing | 2021-04-22 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2022-10-27 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Inherited Neuropathy Consortium | Uncertain significance | no assertion criteria provided | literature only |  |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2015-03-03 |
| 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 |  |

## 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, 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](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease/).

**Reported phenotype names (ClinVar):** Charcot-Marie-Tooth disease recessive intermediate A, not specified, Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive, Charcot-Marie-Tooth disease type 4A, Charcot-Marie-Tooth disease, not provided, Charcot-Marie-Tooth disease axonal type 2K, AllHighlyPenetrant, none provided, CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL RECESSIVE, TYPE 2K.

## Similar variants {#similar}

Related GDAP1 variant pages (same residue, condition, or type): [GDAP1 p.Ser169Phe](/variant/gdap1-p-ser169phe), [GDAP1 p.Ser169Leu](/variant/gdap1-p-ser169leu), [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 261065). 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.*