Is PEX6 p.Val181= (c.543G>A) pathogenic?

PEX6 p.Val181= (c.543G>A) is classified Conflicting classifications of pathogenicity in PEX6 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-30). Ultra-rare (popmax 0.0321%, afr); Associated with peroxisome biogenesis disorder.

What condition is associated with PEX6 p.Val181= (c.543G>A)?

PEX6 p.Val181= (c.543G>A) is associated with peroxisome biogenesis disorder, Zellweger spectrum disorders (ClinVar).

How common is PEX6 p.Val181= (c.543G>A) in the general population?

PEX6 p.Val181= (c.543G>A) is ultra-rare (popmax 0.0321%, afr) (gnomAD).

PEX6 p.Val181=

c.543G>A · rs368560418 · VCV951387

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0321%, afr)

Conditions

peroxisome biogenesis disorder

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 -0.36	GERP -0.63, phastCons 0.023
Overall
CADD	8.804	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0321% African / African-American · 24/74,784 alleles

Filtering AF 0.022% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0188%

Overall 0.00199% 32/1,605,812 alleles · ultra-rare exomes 13/1,453,626 · genomes 19/152,186 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0321%	3,116
Admixed American	0.0118%	8,480
Remaining individualsnot grpmax-eligible	0.00161%	62,270

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.Val181=
Coding: c.543G>A
MANE Select: NM_000287
dbSNP: rs368560418
Type: single nucleotide variant
Location: chr6:42978608 (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 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Zellweger spectrum disorders

Similar variants

PEX6 p.Val181Met Uncertain significance ★★ ⚠ same residue
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.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-val181 (accessed [today's date]).

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