# NM_018972.4(GDAP1):c.121C>A (p.Arg41Ser)

https://sugi.bio/variant/gdap1-p-arg41ser

## Summary

**GDAP1 p.Arg41Ser (c.121C>A)** is classified **Uncertain significance** in GDAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-19). AlphaMissense: likely pathogenic (0.997); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease type 4A.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the GDAP1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, 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.Arg41Ser |
| Coding change (HGVS c.) | c.121C>A |
| MANE Select transcript | [NM_018972](https://www.ncbi.nlm.nih.gov/nuccore/NM_018972) |
| Variant type | single nucleotide variant |
| Location | chr8:74351277-74351277 (GRCh38) |
| ClinVar | [VCV3641961](https://www.ncbi.nlm.nih.gov/clinvar/variation/3641961/) |

**All HGVS expressions:** `LRG_244:g.35148C>A`, `LRG_244t1:c.121C>A`, `NC_000008.10:g.75263512C>A`, `NC_000008.11:g.74351277C>A`, `NG_008787.3:g.35148C>A`, `NM_001040875.4:c.-63-21C>A`, `NM_001362929.2:c.-62C>A`, `NM_001362930.2:c.121C>A`, `NM_001362931.2:c.121C>A`, `NM_001362932.2:c.-18+699C>A`, `NM_018972.4:c.121C>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.997)
- REVEL 0.49 (indeterminate)
- SaProt LLR -11.836 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL is indeterminate
- SpliceAI predicts **donor loss** (Δ 0.25) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.59, GERP 2.3, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 3%** most-pathogenic-predicted substitutions in GDAP1 (of 2,090 modeled).
- CADD: **PHRED 33.0**. 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 deltas (raw): acceptor loss **0.17**, donor loss **0.25**, acceptor gain **0.00**, donor gain **0.03**. Largest is donor loss, 44 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.03**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.27** (loss), gain 0.02 / loss 0.27. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- 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 **41** lies in the gst n-terminal domain; an α-helix.

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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-02-19.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-02-19 |

## 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, Charcot-Marie-Tooth disease, demyelinating, autosomal recessive, type 4a.

## Similar variants {#similar}

Related GDAP1 variant pages (same residue, condition, or type): [GDAP1 p.Arg41=](/variant/gdap1-p-arg41), [GDAP1 p.Arg41Leu](/variant/gdap1-p-arg41leu), [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 2026-10-15); 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 3641961). 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.*