Is GDAP1 p.Pro274Leu (c.821C>T) pathogenic?

GDAP1 p.Pro274Leu (c.821C>T) is classified Conflicting classifications of pathogenicity in GDAP1 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2016-01-06). AlphaMissense: likely benign (0.1726); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease axonal type 2K.

What condition is associated with GDAP1 p.Pro274Leu (c.821C>T)?

GDAP1 p.Pro274Leu (c.821C>T) is associated with Charcot-Marie-Tooth disease axonal type 2K (ClinVar).

How common is GDAP1 p.Pro274Leu (c.821C>T) in the general population?

GDAP1 p.Pro274Leu (c.821C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GDAP1 p.Pro274Leu (c.821C>T)?

AlphaMissense predicts likely benign (score 0.1726) — an in-silico prediction, not a clinical call.

GDAP1 p.Pro274Leu

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.821C>T · rs397515443 · VCV50559

Conflicting classifications of pathogenicity No assertion criteria

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1726 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease axonal type 2K

Computational evidence

Protein change
AlphaMissense	0.1726	likely benign
REVEL	0.719	pathogenic-leaning
SaProt	LLR -7.61	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do 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	26.4	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

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.Pro274Leu
Coding: c.821C>T
MANE Select: NM_018972
dbSNP: rs397515443
Type: single nucleotide variant
Location: chr8:74364111 (GRCh38)
Gene constraint: LOEUF 0.963 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.68 · 8 PDB
Residue 274: 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 axonal type 2K — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

GDAP1 p.Pro274Ala 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.Arg282Cys Pathogenic ★★ same condition
GDAP1 p.Arg310Gln 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-pro274leu (accessed [today's date]).

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