Is PEX6 p.Leu9= (c.25C>T) pathogenic?

PEX6 p.Leu9= (c.25C>T) is classified Conflicting classifications of pathogenicity in PEX6 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-02-02). Rare (popmax 0.105%, eas); Associated with peroxisome biogenesis disorder 4A (Zellweger).

What condition is associated with PEX6 p.Leu9= (c.25C>T)?

PEX6 p.Leu9= (c.25C>T) is associated with peroxisome biogenesis disorder 4A (Zellweger), peroxisome biogenesis disorder, Zellweger spectrum disorders (ClinVar).

How common is PEX6 p.Leu9= (c.25C>T) in the general population?

PEX6 p.Leu9= (c.25C>T) is rare (popmax 0.105%, eas) (gnomAD).

PEX6 p.Leu9=

c.25C>T · rs183449855 · VCV502417

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.105%, eas)

Conditions

peroxisome biogenesis disorder 4A (Zellweger)

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 3.4	GERP -0.72, phastCons 1
Overall
CADD	10.42	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.105% East Asian · 46/43,650 alleles

Filtering AF 0.0811% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0726%

Overall 0.0126% 198/1,575,948 alleles · rare exomes 148/1,423,612 · genomes 50/152,336 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.105%	949
Remaining individualsnot grpmax-eligible	0.0847%	1,180
African / African-American	0.0631%	1,585
South Asian	0.0536%	1,866
European (non-Finnish)	0.000513%	194,956

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: PEX6
Protein: p.Leu9=
Coding: c.25C>T
MANE Select: NM_000287
dbSNP: rs183449855
Type: single nucleotide variant
Location: chr6:42979126 (GRCh38)
Gene constraint: LOEUF 0.799 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.87

Full PEX6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

peroxisome biogenesis disorder 4A (Zellweger) — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: peroxisome biogenesis disorder Zellweger spectrum disorders

Similar variants

PEX6 c.1130+1G>A Likely pathogenic ★★ same condition
PEX6 c.1233+1G>A Likely pathogenic ★★ same condition
PEX6 c.1688+1G>A Pathogenic ★★ same condition
PEX6 c.1689-1G>A Likely pathogenic ★★ same condition
PEX6 c.1885-1G>A Likely pathogenic ★★ same condition
PEX6 c.1961+1G>A Likely pathogenic ★★ same condition
PEX6 c.1962-1G>A Pathogenic/Likely pathogenic ★★ same condition
PEX6 c.2094+1G>A Likely pathogenic ★★ 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/pex6-p-leu9 (accessed [today's date]).

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