Is GDAP1 p.Leu251= (c.753C>T) pathogenic?

GDAP1 p.Leu251= (c.753C>T) is classified Likely benign in GDAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-14). Very rare (popmax 0.0022%, sas); Associated with Charcot-Marie-Tooth disease type 4A.

What condition is associated with GDAP1 p.Leu251= (c.753C>T)?

GDAP1 p.Leu251= (c.753C>T) is associated with Charcot-Marie-Tooth disease type 4A (ClinVar).

How common is GDAP1 p.Leu251= (c.753C>T) in the general population?

GDAP1 p.Leu251= (c.753C>T) 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.

GDAP1 p.Leu251=

c.753C>T · rs1285748573 · VCV1159171

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

Charcot-Marie-Tooth disease type 4A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.8	GERP -5.5
Overall
CADD	1.025	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,080 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000744% 12/1,613,948 alleles · very rare exomes 12/1,461,728 · genomes 0/152,220 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,540
Admixed American	0.00167%	60,020
European (non-Finnish)	0.000763%	131,095

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.Leu251=
Coding: c.753C>T
MANE Select: NM_018972
dbSNP: rs1285748573
Type: single nucleotide variant
Location: chr8:74364043 (GRCh38)
Gene constraint: LOEUF 0.963 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.68 · 8 PDB
Residue 251: 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 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.Leu251Val 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.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-leu251 (accessed [today's date]).

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