Is GDAP1 p.Ile348Val (c.1042A>G) pathogenic?

GDAP1 p.Ile348Val (c.1042A>G) is classified Uncertain significance in GDAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-05-04). AlphaMissense: likely benign (0.0671); Very rare (popmax 0.0011%, sas); Associated with Charcot-Marie-Tooth disease type 4A.

What condition is associated with GDAP1 p.Ile348Val (c.1042A>G)?

GDAP1 p.Ile348Val (c.1042A>G) is associated with Charcot-Marie-Tooth disease type 4A (ClinVar).

How common is GDAP1 p.Ile348Val (c.1042A>G) in the general population?

GDAP1 p.Ile348Val (c.1042A>G) is very rare (popmax 0.0011%, sas) (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.Ile348Val (c.1042A>G)?

AlphaMissense predicts likely benign (score 0.0671) — an in-silico prediction, not a clinical call.

GDAP1 p.Ile348Val

c.1042A>G · rs775559344 · VCV1516374

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0671 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 4A

Computational evidence

Protein change
AlphaMissense	0.0671	likely benign
REVEL	0.255	benign-leaning
SaProt	LLR -6.20	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.53	GERP -4.9, phastCons 0.89
Regional constraint	o/e 0.86	unconstrained · MANE · 14 kb · p 0.0041 · regional, not allelic
Overall
CADD	10.53	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,074 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000743% 12/1,614,034 alleles · very rare exomes 12/1,461,794 · genomes 0/152,240 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,074
European (non-Finnish)	0.000932%	107,269

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.Ile348Val
Coding: c.1042A>G
MANE Select: NM_018972
dbSNP: rs775559344
Type: single nucleotide variant
Location: chr8:74364332 (GRCh38)
Gene constraint: LOEUF 0.963 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.68 · 8 PDB
Residue 348: the 'required for mitochondrial localization' region

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

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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
GDAP1 p.Arg257Ter 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-ile348val (accessed [today's date]).

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