Is GDAP1 p.Met1Val (c.1A>G) pathogenic?

GDAP1 p.Met1Val (c.1A>G) is classified Pathogenic in GDAP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-10). Very rare (popmax 0.0011%, sas); Associated with Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive.

What condition is associated with GDAP1 p.Met1Val (c.1A>G)?

GDAP1 p.Met1Val (c.1A>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.Met1Val (c.1A>G) in the general population?

GDAP1 p.Met1Val (c.1A>G) is very rare (popmax 0.0011%, sas) (gnomAD).

GDAP1 p.Met1Val

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.1A>G · rs1474390668 · VCV2423924

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

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	start-loss	predicted loss-of-function
REVEL	0.605	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9	GERP 0.8, phastCons 1
Overall
CADD	21.1	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 0.0011% South Asian · 1/90,852 alleles

Overall 0.000125% 2/1,601,530 alleles · very rare exomes 2/1,449,192 · genomes 0/152,338 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00161%	62,106
South Asiangrpmax	0.0011%	90,852

Remaining individuals shows a higher raw frequency than the grpmax group above it. 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.

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.Met1Val
Coding: c.1A>G
MANE Select: NM_018972
dbSNP: rs1474390668
Type: single nucleotide variant
Location: chr8:74350462 (GRCh38)
Gene constraint: LOEUF 0.963 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.68 · 8 PDB

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.Met1Leu Conflicting classifications of pathogenicity same residue
GDAP1 p.Met1fs Pathogenic/Likely 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

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-met1val (accessed [today's date]).

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