Is GDAP1 p.Pro231Leu (c.692C>T) pathogenic?

GDAP1 p.Pro231Leu (c.692C>T) is classified Pathogenic/Likely pathogenic in GDAP1 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2025-09-18). AlphaMissense: likely benign (0.1648); Ultra-rare (popmax 0.0571%, amr); Associated with Charcot-Marie-Tooth disease axonal type 2K.

What condition is associated with GDAP1 p.Pro231Leu (c.692C>T)?

GDAP1 p.Pro231Leu (c.692C>T) is associated with Charcot-Marie-Tooth disease axonal type 2K, Charcot-Marie-Tooth disease type 4A, Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive (ClinVar).

How common is GDAP1 p.Pro231Leu (c.692C>T) in the general population?

GDAP1 p.Pro231Leu (c.692C>T) is ultra-rare (popmax 0.0571%, amr) (gnomAD).

What do computational predictors say about GDAP1 p.Pro231Leu (c.692C>T)?

AlphaMissense predicts likely benign (score 0.1648) — an in-silico prediction, not a clinical call.

GDAP1 p.Pro231Leu

Q: How is Autosomal recessive Charcot-Marie-Tooth disease with hoarseness inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.692C>T · rs121908114 · VCV4202

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.1648 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0571%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease axonal type 2K

Computational evidence

Protein change
AlphaMissense	0.1648	likely benign ⚠ discordant with ClinVar
REVEL	0.704	pathogenic-leaning
SaProt	LLR -10.44	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 14 kb · p 0.0041 · regional, not allelic
Overall
CADD	31.0	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 0.0571% Admixed American · 34/59,582 alleles

Filtering AF 0.0419% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0368%

Overall 0.00312% 41/1,312,330 alleles · ultra-rare exomes 16/1,160,338 · genomes 25/151,992 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0571%	1,752
Remaining individualsnot grpmax-eligible	0.0114%	8,752
European (non-Finnish)	0.000111%	904,740

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.Pro231Leu
Coding: c.692C>T
MANE Select: NM_018972
dbSNP: rs121908114
Type: single nucleotide variant
Location: chr8:74363051 (GRCh38)
Gene constraint: LOEUF 0.963 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.68 · 8 PDB
Residue 231: the gst c-terminal domain

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

Disease context

Charcot-Marie-Tooth disease axonal type 2K — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Charcot-Marie-Tooth disease type 4A Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive Charcot-Marie-Tooth disease recessive intermediate A Charcot-Marie-Tooth disease

For Autosomal recessive Charcot-Marie-Tooth disease with hoarseness (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

GDAP1 p.Pro231= Conflicting classifications of pathogenicity ★ same residue
GDAP1 p.Pro231Ser 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

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-pro231leu (accessed [today's date]).

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