Is GDAP1 p.Leu239Phe (c.715C>T) pathogenic?

GDAP1 p.Leu239Phe (c.715C>T) is classified Pathogenic/Likely pathogenic in GDAP1 (ClinVar, Multiple submitters, 19 submitters; last evaluated 2025-11-03). AlphaMissense: likely pathogenic (0.9096); Very rare (popmax 0.00568%, nfe); Associated with GDAP1-related disorder.

What condition is associated with GDAP1 p.Leu239Phe (c.715C>T)?

GDAP1 p.Leu239Phe (c.715C>T) is associated with GDAP1-related disorder, polyneuropathy, sensory peripheral neuropathy (ClinVar).

How common is GDAP1 p.Leu239Phe (c.715C>T) in the general population?

GDAP1 p.Leu239Phe (c.715C>T) is very rare (popmax 0.00568%, nfe) (gnomAD).

What do computational predictors say about GDAP1 p.Leu239Phe (c.715C>T)?

AlphaMissense predicts likely pathogenic (score 0.9096) — an in-silico prediction, not a clinical call.

GDAP1 p.Leu239Phe

c.715C>T · rs104894080 · VCV4200

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 19 submitters

AlphaMissense

likely pathogenic

0.9096 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00568%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

GDAP1-related disorder

Computational evidence

Protein change
AlphaMissense	0.9096	likely pathogenic ✓ concordant with ClinVar
REVEL	0.882	moderately pathogenic-leaning
SaProt	LLR -8.14	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.8, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 14 kb · p 0.0041 · regional, not allelic
Overall
CADD	27.3	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 0.00568% European (non-Finnish) · 67/1,179,932 alleles

Filtering AF 0.00454% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00417%

Overall 0.00428% 69/1,613,944 alleles · very rare exomes 62/1,461,768 · genomes 7/152,176 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00568%	17,611
Remaining individualsnot grpmax-eligible	0.0032%	31,241

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.Leu239Phe
Coding: c.715C>T
MANE Select: NM_018972
dbSNP: rs104894080
Type: single nucleotide variant
Location: chr8:74364005 (GRCh38)
Gene constraint: LOEUF 0.963 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.68 · 8 PDB
Residue 239: the gst c-terminal domain; a β-strand

Full GDAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

GDAP1-related disorder

Also linked: polyneuropathy sensory peripheral neuropathy axonal neuropathy Charcot-Marie-Tooth disease type 4A Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive Charcot-Marie-Tooth disease axonal type 2K Charcot-Marie-Tooth disease recessive intermediate A Charcot-Marie-Tooth disease

Similar variants

GDAP1 p.Leu239Pro Likely pathogenic ★ same residue
GDAP1 p.Leu239His Uncertain significance ★ ⚠ same residue
GDAP1 p.Leu239= Likely benign ★ 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

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-leu239phe (accessed [today's date]).

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