# NM_005391.5(PDK3):c.204G>A (p.Pro68=)

https://sugi.bio/variant/pdk3-p-pro68

## Summary

**PDK3 p.Pro68= (c.204G>A)** is classified **Benign/Likely benign** in PDK3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-01). Ultra-rare (popmax 0.0332%, afr); Associated with Charcot-Marie-Tooth disease X-linked dominant 6.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs201536570 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0332%, afr)

## For patients & families {#patients}

This is a change in the PDK3 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to Charcot-Marie-Tooth disease X-linked dominant 6.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | X-linked dominant |
| Age of onset (of this condition) | Childhood |
| Diagnostic panels | PDK3 is a diagnostic-grade gene on 6 Genomics England panels |

**Commonly reported features of X-linked Charcot-Marie-Tooth disease type 6** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Decreased nerve conduction velocity — Very frequent (99-80%)
- Gait disturbance — Very frequent (99-80%)
- Pes cavus — Very frequent (99-80%)
- Hand tremor — Very frequent (99-80%)
- Distal sensory impairment — Very frequent (99-80%)
- Absent Achilles reflex — Very frequent (99-80%)
- EMG: axonal abnormality — Very frequent (99-80%)
- Sensorimotor neuropathy — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012445/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PDK3](https://sugi.bio/atlas/gene/PDK3/) |
| Protein change (HGVS p.) | p.Pro68= |
| Coding change (HGVS c.) | c.204G>A |
| MANE Select transcript | [NM_005391](https://www.ncbi.nlm.nih.gov/nuccore/NM_005391) |
| dbSNP | [rs201536570](https://www.ncbi.nlm.nih.gov/snp/rs201536570/) |
| Variant type | single nucleotide variant |
| Location | chrX:24494839-24494839 (GRCh38) |
| ClinVar | [VCV1164809](https://www.ncbi.nlm.nih.gov/clinvar/variation/1164809/) |

**All HGVS expressions:** `NC_000023.10:g.24512956G>A`, `NC_000023.11:g.24494839G>A`, `NG_016762.1:g.34613G>A`, `NM_001142386.3:c.204G>A`, `NM_005391.5:c.204G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -7.937, GERP -4.98 — fast-evolving / accelerated position
- CADD: **PHRED 0.734**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0332%** (afr) · FAF95 0.0217% · FAF99 0.0181% · 19/57,160 in the highest group · 39/1,204,624 alleles overall — ultra-rare (popmax 0.0332%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0332% | 3,008 |
| Middle Eastern | 0.023% | 4,341 |
| Remaining individuals (not grpmax-eligible) | 0.0127% | 7,903 |
| South Asian | 0.00711% | 14,056 |
| East Asian | 0.00297% | 33,702 |
| Admixed American | 0.00221% | 45,289 |
| European (non-Finnish) | 0.000785% | 127,318 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}


Curated gene–disease validity (ClinGen):

- **Charcot-Marie-Tooth disease X-linked dominant 6** — Definitive (XL)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 91.32, 81% of residues very-high.

**5 experimental structure(s)** (PDB): [1Y8N](https://www.rcsb.org/structure/1Y8N), [1Y8O](https://www.rcsb.org/structure/1Y8O), [1Y8P](https://www.rcsb.org/structure/1Y8P), [2PNR](https://www.rcsb.org/structure/2PNR), [2Q8I](https://www.rcsb.org/structure/2Q8I).

## What this gene does {#gene-function}

*Describes the biological roles of PDK3 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** PDK3's established molecular role includes protein kinase activity.


### Pathways affected {#pathways}

PDK3 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Regulation of pyruvate dehydrogenase (PDH) complex](https://reactome.org/content/detail/R-HSA-204174) | curated |
| [Signaling by Retinoic Acid](https://reactome.org/content/detail/R-HSA-5362517) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** protein kinase activity, protein serine/threonine kinase activity, pyruvate dehydrogenase (acetyl-transferring) kinase activity, ATP binding.

**Biological process:** regulation of pyruvate decarboxylation to acetyl-CoA, regulation of glucose metabolic process, peptidyl-serine phosphorylation, peroxisome proliferator activated receptor signaling pathway, cellular response to fatty acid, hypoxia-inducible factor-1alpha signaling pathway.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-09-01.

**Submitter consensus:** conflicting (1 Benign, 1 Likely benign).

**Submission history:** 2 submissions (2022–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2022-11-08 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-01 |

## Associated conditions {#conditions}

[Charcot-Marie-Tooth disease X-linked dominant 6](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-x-linked-dominant-6/).

**Reported phenotype names (ClinVar):** Charcot-Marie-Tooth disease X-linked dominant 6, not provided, CHARCOT-MARIE-TOOTH NEUROPATHY, X-LINKED DOMINANT, 6, none provided.

## Similar variants {#similar}

Related PDK3 variant pages (same residue, condition, or type): [PDK3 p.Pro68Leu](/variant/pdk3-p-pro68leu), [PDK3 c.320+6T>C](/variant/pdk3-c-320-plus-6t-c), [PDK3 p.Ala360Val](/variant/pdk3-p-ala360val), [PDK3 p.Arg378Cys](/variant/pdk3-p-arg378cys), [PDK3 p.Asp188Asn](/variant/pdk3-p-asp188asn), [PDK3 p.Ile113Thr](/variant/pdk3-p-ile113thr), [PDK3 p.Leu112Pro](/variant/pdk3-p-leu112pro), [PDK3 p.Pro141Leu](/variant/pdk3-p-pro141leu).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1164809). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*