Is GDAP1 p.Ser57Arg (c.169A>C) pathogenic?

GDAP1 p.Ser57Arg (c.169A>C) is classified Conflicting classifications of pathogenicity in GDAP1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-07-16). AlphaMissense: likely pathogenic (0.9942); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease type 4A.

What condition is associated with GDAP1 p.Ser57Arg (c.169A>C)?

GDAP1 p.Ser57Arg (c.169A>C) is associated with Charcot-Marie-Tooth disease type 4A (ClinVar).

How common is GDAP1 p.Ser57Arg (c.169A>C) in the general population?

GDAP1 p.Ser57Arg (c.169A>C) is absent from gnomAD v4.1 (gnomAD).

How is Charcot-Marie-Tooth disease type 4A inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about GDAP1 p.Ser57Arg (c.169A>C)?

AlphaMissense predicts likely pathogenic (score 0.9942) — an in-silico prediction, not a clinical call.

GDAP1 p.Ser57Arg

c.169A>C · rs863224774 · VCV216706

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9942 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Charcot-Marie-Tooth disease type 4A

Computational evidence

Protein change
AlphaMissense	0.9942	likely pathogenic · top 5% in GDAP1
REVEL	0.397	indeterminate
SaProt	LLR -5.94	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.51	donor loss, 4 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 14 kb · p 0.0041 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GDAP1
Protein: p.Ser57Arg
Coding: c.169A>C
MANE Select: NM_018972
dbSNP: rs863224774
Type: single nucleotide variant
Location: chr8:74351325 (GRCh38)
Gene constraint: LOEUF 0.963 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.68 · 8 PDB
Residue 57: the gst n-terminal domain

Full GDAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease type 4A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Charcot-Marie-Tooth disease type 4A (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

GDAP1 p.Ser57fs Pathogenic ★ same residue
GDAP1 c.311-1G>A Pathogenic/Likely pathogenic ★★ same condition
GDAP1 c.579+1G>A Pathogenic ★★ same condition
GDAP1 c.694+1G>A Pathogenic/Likely pathogenic ★★ same condition
GDAP1 p.Arg120Trp Pathogenic ★★ ⚠ same condition
GDAP1 p.Arg125Ter Pathogenic ★★ same condition
GDAP1 p.Arg161His Pathogenic/Likely pathogenic ★★ ⚠ same condition
GDAP1 p.Arg191Ter Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/gdap1-p-ser57arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown