Is PEX6 p.Pro455= (c.1365A>G) pathogenic?

PEX6 p.Pro455= (c.1365A>G) is classified Conflicting classifications of pathogenicity in PEX6 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-08-25). Very rare (popmax 0.00864%, nfe); Associated with peroxisome biogenesis disorder 4A (Zellweger).

What condition is associated with PEX6 p.Pro455= (c.1365A>G)?

PEX6 p.Pro455= (c.1365A>G) is associated with peroxisome biogenesis disorder 4A (Zellweger), peroxisome biogenesis disorder, Zellweger spectrum disorders (ClinVar).

How common is PEX6 p.Pro455= (c.1365A>G) in the general population?

PEX6 p.Pro455= (c.1365A>G) is very rare (popmax 0.00864%, nfe) (gnomAD).

PEX6 p.Pro455=

c.1365A>G · rs759402659 · VCV765698

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00864%, nfe)

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 -4.1	GERP -2.8
Overall
CADD	2.747	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00864% European (non-Finnish) · 102/1,180,000 alleles

Filtering AF 0.00724% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00676%

Overall 0.00657% 106/1,612,554 alleles · very rare exomes 104/1,460,420 · genomes 2/152,134 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00864%	11,569
Remaining individualsnot grpmax-eligible	0.00321%	31,176
East Asian	0.00223%	44,886
South Asian	0.0011%	91,020

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.Pro455=
Coding: c.1365A>G
MANE Select: NM_000287
dbSNP: rs759402659
Type: single nucleotide variant
Location: chr6:42969670 (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-pro455 (accessed [today's date]).

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