Is GDAP1 p.Arg120Gln (c.359G>A) pathogenic?

GDAP1 p.Arg120Gln (c.359G>A) is classified Uncertain significance in GDAP1 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2016-01-06). AlphaMissense: likely pathogenic (0.714); Very rare (popmax 0.0022%, sas); Associated with Charcot-Marie-Tooth disease type 4A.

What condition is associated with GDAP1 p.Arg120Gln (c.359G>A)?

GDAP1 p.Arg120Gln (c.359G>A) is associated with Charcot-Marie-Tooth disease type 4A, Charcot-Marie-Tooth disease (ClinVar).

How common is GDAP1 p.Arg120Gln (c.359G>A) in the general population?

GDAP1 p.Arg120Gln (c.359G>A) is very rare (popmax 0.0022%, 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.Arg120Gln (c.359G>A)?

AlphaMissense predicts likely pathogenic (score 0.714) — an in-silico prediction, not a clinical call.

GDAP1 p.Arg120Gln

c.359G>A · rs1174933176 · VCV637548

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.714 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 4A

Computational evidence

Protein change
AlphaMissense	0.714	likely pathogenic
REVEL	0.77	pathogenic-leaning
SaProt	LLR -5.25	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	Δ0.96	acceptor gain · deltas
Pangolin	Δ0.82	gain · loss 0.52 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 14 kb · p 0.0041 · regional, not allelic
Overall
CADD	35.0	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

Grpmax group 0.0022% South Asian · 2/91,054 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000372% 6/1,613,368 alleles · very rare exomes 6/1,461,194 · genomes 0/152,174 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,527
African / African-American	0.00133%	75,002
European (non-Finnish)	0.000254%	393,127

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.Arg120Gln
Coding: c.359G>A
MANE Select: NM_018972
dbSNP: rs1174933176
Type: single nucleotide variant
Location: chr8:74360185 (GRCh38)
Gene constraint: LOEUF 0.963 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.68 · 8 PDB
Residue 120: a UniProt-annotated variant site (in cmt2k; dominant form); a UniProt-annotated variant site (in cmt4a; no effect on mitochondrial localization but impairment in the ability to induce mitochondrial fragmentation); a UniProt-annotated variant site (in cmt2k; dominant form; no effect on mitochondrial localization); 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

Also linked: Charcot-Marie-Tooth disease

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

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

GDAP1 p.Arg120Trp Pathogenic ★★ ⚠ same residue
GDAP1 p.Arg120Leu Likely pathogenic ★ ⚠ same residue
GDAP1 p.Arg120= Likely benign ★ same residue
GDAP1 p.Arg120Gly Uncertain significance ⚠ 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.Arg125Ter 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-arg120gln (accessed [today's date]).

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