Is GDAP1 p.Ser194Ter (c.581C>G) pathogenic?

GDAP1 p.Ser194Ter (c.581C>G) is classified Pathogenic in GDAP1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-10-05). Very rare (popmax 0.00837%, amr); Associated with Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive.

What condition is associated with GDAP1 p.Ser194Ter (c.581C>G)?

GDAP1 p.Ser194Ter (c.581C>G) is associated with Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive, Charcot-Marie-Tooth disease type 4A, Charcot-Marie-Tooth disease axonal type 2K (ClinVar).

How common is GDAP1 p.Ser194Ter (c.581C>G) in the general population?

GDAP1 p.Ser194Ter (c.581C>G) is very rare (popmax 0.00837%, amr) (gnomAD).

GDAP1 p.Ser194Ter

Q: How is Autosomal recessive intermediate Charcot-Marie-Tooth disease type A inherited?

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

c.581C>G · rs104894075 · VCV4191

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00837%, amr)

Conditions

Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 6
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Overall
CADD	42.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00837% Admixed American · 5/59,720 alleles

Filtering AF 0.00324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000494% 7/1,418,394 alleles · very rare exomes 4/1,266,574 · genomes 3/151,820 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00837%	11,944
Remaining individualsnot grpmax-eligible	0.00358%	27,939

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: GDAP1
Protein: p.Ser194Ter
Coding: c.581C>G
MANE Select: NM_018972
dbSNP: rs104894075
Type: single nucleotide variant
Location: chr8:74362940 (GRCh38)
Gene constraint: LOEUF 0.963 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.68 · 8 PDB
Residue 194: the gst c-terminal domain; an α-helix

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

Disease context

Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Charcot-Marie-Tooth disease type 4A Charcot-Marie-Tooth disease axonal type 2K Charcot-Marie-Tooth disease recessive intermediate A

For Autosomal recessive intermediate Charcot-Marie-Tooth disease type A (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

GDAP1 p.Ser194= Likely benign ★ 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-ser194ter (accessed [today's date]).

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