Is PDK3 p.Arg74= (c.222C>T) pathogenic?

PDK3 p.Arg74= (c.222C>T) is classified Benign in PDK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-29). Ultra-rare (popmax 0.0976%, sas); Associated with Charcot-Marie-Tooth disease X-linked dominant 6.

What condition is associated with PDK3 p.Arg74= (c.222C>T)?

PDK3 p.Arg74= (c.222C>T) is associated with Charcot-Marie-Tooth disease X-linked dominant 6 (ClinVar).

How common is PDK3 p.Arg74= (c.222C>T) in the general population?

PDK3 p.Arg74= (c.222C>T) is ultra-rare (popmax 0.0976%, sas) (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.

PDK3 p.Arg74=

c.222C>T · VCV3671651

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0976%, sas)

Conditions

Charcot-Marie-Tooth disease X-linked dominant 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.12	GERP -3.7, phastCons 0.85
Overall
CADD	8.269	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0976% South Asian · 55/56,333 alleles

Filtering AF 0.077% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0696%

Overall 0.00465% 56/1,204,987 alleles · ultra-rare exomes 53/1,092,808 · genomes 3/112,179 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0976%	1,024
Remaining individualsnot grpmax-eligible	0.00211%	47,426

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: PDK3
Protein: p.Arg74=
Coding: c.222C>T
MANE Select: NM_005391
Type: single nucleotide variant
Location: chrX:24494857 (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 p.Arg74Cys Uncertain significance ★ ⚠ same residue
PDK3 p.Arg74His 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

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-arg74 (accessed [today's date]).

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