Is GDAP1 p.Pro153Leu (c.458C>T) pathogenic?

GDAP1 p.Pro153Leu (c.458C>T) is classified Pathogenic/Likely pathogenic in GDAP1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-11-07). AlphaMissense: likely pathogenic (0.9905); Very rare (popmax 0.005%, amr); Associated with GDAP1-related disorder.

What condition is associated with GDAP1 p.Pro153Leu (c.458C>T)?

GDAP1 p.Pro153Leu (c.458C>T) is associated with GDAP1-related disorder, peripheral neuropathy, Charcot-Marie-Tooth disease type 4A (ClinVar).

How common is GDAP1 p.Pro153Leu (c.458C>T) in the general population?

GDAP1 p.Pro153Leu (c.458C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about GDAP1 p.Pro153Leu (c.458C>T)?

AlphaMissense predicts likely pathogenic (score 0.9905) — an in-silico prediction, not a clinical call.

GDAP1 p.Pro153Leu

c.458C>T · rs538412810 · VCV406135

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.9905 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

GDAP1-related disorder

Computational evidence

Protein change
AlphaMissense	0.9905	likely pathogenic ✓ concordant with ClinVar · top 8% in GDAP1
REVEL	0.902	moderately pathogenic-leaning
SaProt	LLR -12.75	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 14 kb · p 0.0041 · regional, not allelic
Overall
CADD	32.0	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 0.005% Admixed American · 3/60,008 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000991% 16/1,613,894 alleles · very rare exomes 14/1,461,668 · genomes 2/152,226 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,003
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
South Asian	0.00329%	30,357
Remaining individualsnot grpmax-eligible	0.0032%	31,250
Finnishnot grpmax-eligible	0.00156%	64,028
European (non-Finnish)	0.000509%	196,637

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.Pro153Leu
Coding: c.458C>T
MANE Select: NM_018972
dbSNP: rs538412810
Type: single nucleotide variant
Location: chr8:74360284 (GRCh38)
Gene constraint: LOEUF 0.963 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.68 · 8 PDB
Residue 153: the gst c-terminal domain

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

Disease context

GDAP1-related disorder

Also linked: peripheral 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.Pro153Ser Likely pathogenic ★ same residue
GDAP1 p.Pro153= Conflicting classifications of pathogenicity ★ same residue
GDAP1 p.Pro153Gln 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

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-pro153leu (accessed [today's date]).

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