Is PDK3 p.Phe366Cys (c.1097T>G) pathogenic?

PDK3 p.Phe366Cys (c.1097T>G) is classified Uncertain significance in PDK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-09-30). AlphaMissense: ambiguous (0.3963); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease X-linked dominant 6.

What condition is associated with PDK3 p.Phe366Cys (c.1097T>G)?

PDK3 p.Phe366Cys (c.1097T>G) is associated with Charcot-Marie-Tooth disease X-linked dominant 6 (ClinVar).

How common is PDK3 p.Phe366Cys (c.1097T>G) in the general population?

PDK3 p.Phe366Cys (c.1097T>G) is absent from gnomAD v4.1 (gnomAD).

How is X-linked Charcot-Marie-Tooth disease type 6 inherited?

Typically X-linked dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PDK3 p.Phe366Cys (c.1097T>G)?

AlphaMissense predicts ambiguous (score 0.3963) — an in-silico prediction, not a clinical call.

PDK3 p.Phe366Cys

c.1097T>G · rs1922715042 · VCV960314

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3963 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Charcot-Marie-Tooth disease X-linked dominant 6

Computational evidence

Protein change
AlphaMissense	0.3963	ambiguous
REVEL	0.293	indeterminate
SaProt	LLR -4.01	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 69 kb · p 4.5e-13 · regional, not allelic
Overall
CADD	24.8	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: PDK3
Protein: p.Phe366Cys
Coding: c.1097T>G
MANE Select: NM_005391
dbSNP: rs1922715042
Type: single nucleotide variant
Location: chrX:24533948 (GRCh38)
Structure: AlphaFold pLDDT 91.32 · 5 PDB

Full PDK3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease X-linked dominant 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For X-linked Charcot-Marie-Tooth disease type 6 (Orphanet):

Inheritance: X-linked dominant
Onset: Childhood

Similar variants

PDK3 c.320+6T>C Uncertain significance ★★ same condition
PDK3 p.Ala360Val Uncertain significance ★★ ⚠ same condition
PDK3 p.Arg378Cys Uncertain significance ★★ same condition
PDK3 p.Asp188Asn Uncertain significance ★★ ⚠ same condition
PDK3 p.Ile113Thr Uncertain significance ★★ ⚠ same condition
PDK3 p.Leu112Pro Uncertain significance ★★ ⚠ same condition
PDK3 p.Pro141Leu Uncertain significance ★★ ⚠ same condition
PDK3 p.Pro231Arg Uncertain significance ★★ ⚠ 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/pdk3-p-phe366cys (accessed [today's date]).

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