Is PDXK p.Pro129= (c.387G>A) pathogenic?

PDXK p.Pro129= (c.387G>A) is classified Benign in PDXK (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-11-28). Common (popmax 22.4%, eas) — too common for a highly-penetrant pathogenic allele; Associated with neuropathy, hereditary motor and sensory, type VIc, with optic atrophy.

What condition is associated with PDXK p.Pro129= (c.387G>A)?

PDXK p.Pro129= (c.387G>A) is associated with neuropathy, hereditary motor and sensory, type VIc, with optic atrophy (ClinVar).

How is Hereditary motor and sensory neuropathy type 6 inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

PDXK p.Pro129=

Q: How common is PDXK p.Pro129= (c.387G>A) in the general population?

PDXK p.Pro129= (c.387G>A) is common (popmax 22.4%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.387G>A · rs11539534 · VCV1268466

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 22.4%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

neuropathy, hereditary motor and sensory, type VIc, with optic atrophy

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 -12	GERP -3.6
Overall
CADD	1.656	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 22.4% East Asian · 10,050/44,786 alleles

Filtering AF 22.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 21.9%

Overall 9.83% 157,746/1,604,982 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	22.4%	4
Admixed American	22.1%	5
South Asian	20.1%	5
Middle Eastern	19.3%	5
Remaining individualsnot grpmax-eligible	10.7%	9
Ashkenazi Jewishnot grpmax-eligible	9.91%	10
Finnishnot grpmax-eligible	9.22%	11
European (non-Finnish)	8.1%	12
African / African-American	6.1%	16
Amishnot grpmax-eligible	5.04%	20

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: PDXK
Protein: p.Pro129=
Coding: c.387G>A
MANE Select: NM_003681
dbSNP: rs11539534
Type: single nucleotide variant
Location: chr21:43749003 (GRCh38)
Gene constraint: LOEUF 0.597 · pLI 0.77 (gnomAD)
Structure: AlphaFold pLDDT 95.83 · 10 PDB

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

Disease context

neuropathy, hereditary motor and sensory, type VIc, with optic atrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary motor and sensory neuropathy type 6 (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages

Similar variants

PDXK p.Pro129Leu Uncertain significance ★ ⚠ same residue
PDXK p.Ala228Thr Pathogenic ★★ ⚠ same condition
PDXK p.Gly281Glu Uncertain significance ★★ ⚠ same condition
PDXK c.331+26T>G Benign ★★ same condition
PDXK c.*14T>C Benign ★★ same condition
PDXK p.Ser125Leu Likely benign ★★ same condition
PDXK p.Asn75Lys Likely pathogenic ★ ⚠ same condition
PDXK p.Arg170Gln 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/pdxk-p-pro129 (accessed [today's date]).

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