Is PDK3 p.Val274Phe (c.820G>T) pathogenic?

PDK3 p.Val274Phe (c.820G>T) is classified Uncertain significance in PDK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-04). AlphaMissense: likely pathogenic (0.7589); No allele count reported in gnomAD v4.1 (AN 1,172,311); Associated with Charcot-Marie-Tooth disease X-linked dominant 6.

What condition is associated with PDK3 p.Val274Phe (c.820G>T)?

PDK3 p.Val274Phe (c.820G>T) is associated with Charcot-Marie-Tooth disease X-linked dominant 6 (ClinVar).

How common is PDK3 p.Val274Phe (c.820G>T) in the general population?

PDK3 p.Val274Phe (c.820G>T) is no allele count reported in gnomAD v4.1 (AN 1,172,311) (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.Val274Phe (c.820G>T)?

AlphaMissense predicts likely pathogenic (score 0.7589) — an in-silico prediction, not a clinical call.

PDK3 p.Val274Phe

c.820G>T · VCV4760577

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7589 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,172,311)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Charcot-Marie-Tooth disease X-linked dominant 6

Computational evidence

Protein change
AlphaMissense	0.7589	likely pathogenic
REVEL	0.61	indeterminate
SaProt	LLR -13.47	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 69 kb · p 4.5e-13 · regional, not allelic
Overall
CADD	26.1	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

No allele count reported in gnomAD v4.1 (AN 1,172,311). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: PDK3
Protein: p.Val274Phe
Coding: c.820G>T
MANE Select: NM_005391
Type: single nucleotide variant
Location: chrX:24527643 (GRCh38)
Structure: AlphaFold pLDDT 91.32 · 5 PDB
Residue 274: the histidine kinase domain; a β-strand

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 p.Val274Ile Uncertain significance ★ ⚠ same residue
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

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-val274phe (accessed [today's date]).

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