Is PDK3 p.Ser375= (c.1125C>T) pathogenic?

PDK3 p.Ser375= (c.1125C>T) is classified Likely benign in PDK3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-01). Very rare (popmax 0.00534%, sas); Associated with Charcot-Marie-Tooth disease X-linked dominant 6.

What condition is associated with PDK3 p.Ser375= (c.1125C>T)?

PDK3 p.Ser375= (c.1125C>T) is associated with Charcot-Marie-Tooth disease X-linked dominant 6 (ClinVar).

How common is PDK3 p.Ser375= (c.1125C>T) in the general population?

PDK3 p.Ser375= (c.1125C>T) is very rare (popmax 0.00534%, 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.Ser375=

c.1125C>T · rs772546760 · VCV1097604

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00534%, 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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.9	GERP -4.2
Overall
CADD	0.079	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% South Asian · 3/56,191 alleles

Filtering AF 0.00142% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000693%

Overall 0.000663% 8/1,206,702 alleles · very rare exomes 7/1,094,905 · genomes 1/111,797 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00534%	18,730
African / African-American	0.00175%	57,065
European (non-Finnish)	0.000448%	223,312

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.Ser375=
Coding: c.1125C>T
MANE Select: NM_005391
dbSNP: rs772546760
Type: single nucleotide variant
Location: chrX:24533976 (GRCh38)
Structure: AlphaFold pLDDT 91.32 · 5 PDB
Residue 375: an α-helix

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-ser375 (accessed [today's date]).

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