Is GDAP1 p.Pro111His (c.332C>A) pathogenic?

GDAP1 p.Pro111His (c.332C>A) is classified Uncertain significance in GDAP1 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2016-01-06). AlphaMissense: likely pathogenic (0.9542); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease axonal type 2K.

What condition is associated with GDAP1 p.Pro111His (c.332C>A)?

GDAP1 p.Pro111His (c.332C>A) is associated with Charcot-Marie-Tooth disease axonal type 2K, Charcot-Marie-Tooth disease (ClinVar).

How common is GDAP1 p.Pro111His (c.332C>A) in the general population?

GDAP1 p.Pro111His (c.332C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GDAP1 p.Pro111His (c.332C>A)?

AlphaMissense predicts likely pathogenic (score 0.9542) — an in-silico prediction, not a clinical call.

GDAP1 p.Pro111His

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.332C>A · rs1586802999 · VCV637551

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9542 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease axonal type 2K

Computational evidence

Protein change
AlphaMissense	0.9542	likely pathogenic
REVEL	0.745	pathogenic-leaning
SaProt	LLR -13.38	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
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	27.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GDAP1
Protein: p.Pro111His
Coding: c.332C>A
MANE Select: NM_018972
dbSNP: rs1586802999
Type: single nucleotide variant
Location: chr8:74360158 (GRCh38)
Gene constraint: LOEUF 0.963 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.68 · 8 PDB

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

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

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

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.Arg191Ter Pathogenic/Likely pathogenic ★★ same condition
GDAP1 p.Arg257Ter Pathogenic/Likely pathogenic ★★ same condition
GDAP1 p.Arg282Cys 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-pro111his (accessed [today's date]).

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