Is GDAP1 p.Met133Val (c.397A>G) pathogenic?

GDAP1 p.Met133Val (c.397A>G) is classified Uncertain significance in GDAP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-30). AlphaMissense: likely benign (0.099); Very rare (popmax 0.000339%, nfe); Associated with Charcot-Marie-Tooth disease type 4A.

What condition is associated with GDAP1 p.Met133Val (c.397A>G)?

GDAP1 p.Met133Val (c.397A>G) is associated with Charcot-Marie-Tooth disease type 4A (ClinVar).

How common is GDAP1 p.Met133Val (c.397A>G) in the general population?

GDAP1 p.Met133Val (c.397A>G) is very rare (popmax 0.000339%, nfe) (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.Met133Val (c.397A>G)?

AlphaMissense predicts likely benign (score 0.099) — an in-silico prediction, not a clinical call.

GDAP1 p.Met133Val

c.397A>G · VCV3379825

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.099 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 4A

Computational evidence

Protein change
AlphaMissense	0.099	likely benign
REVEL	0.658	pathogenic-leaning
SaProt	LLR -6.64	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 2.1, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 14 kb · p 0.0041 · regional, not allelic
Overall
CADD	21.3	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

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,168 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.0013% 21/1,613,090 alleles · very rare exomes 20/1,460,930 · genomes 1/152,160 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0507%	1,973
Remaining individualsnot grpmax-eligible	0.0016%	62,444
Finnishnot grpmax-eligible	0.00156%	64,036
European (non-Finnish)grpmax	0.000339%	294,792

Ashkenazi Jewish 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.Met133Val
Coding: c.397A>G
MANE Select: NM_018972
Type: single nucleotide variant
Location: chr8:74360223 (GRCh38)
Gene constraint: LOEUF 0.963 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.68 · 8 PDB
Residue 133: an α-helix

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.Met133Ile Conflicting classifications of pathogenicity ★ 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-met133val (accessed [today's date]).

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