Is PEX2 p.Leu166fs (c.496_497del) pathogenic?

PEX2 p.Leu166fs (c.496497del) is classified Likely pathogenic in PEX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-12). Very rare (popmax 0.00446%, eas); Associated with Zellweger spectrum disorders.

What condition is associated with PEX2 p.Leu166fs (c.496_497del)?

PEX2 p.Leu166fs (c.496_497del) is associated with Zellweger spectrum disorders (ClinVar).

How common is PEX2 p.Leu166fs (c.496_497del) in the general population?

PEX2 p.Leu166fs (c.496_497del) is very rare (popmax 0.00446%, eas) (gnomAD).

How is Zellweger syndrome inherited?

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

PEX2 p.Leu166fs

c.496_497del · VCV4059612

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

Zellweger spectrum disorders

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (4 of 4) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.7	GERP 1.6, phastCons 1
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,884 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000124% 2/1,614,076 alleles · very rare exomes 1/1,461,794 · genomes 1/152,282 · joint denominator

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: PEX2
Protein: p.Leu166fs
Coding: c.496_497del
MANE Select: NM_000318
Type: Deletion
Location: chr8:76983682 (GRCh38)
Gene constraint: LOEUF 1.057 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.17
Residue 166: a UniProt-annotated variant site (in pbd5a); a UniProt-annotated variant site (in pbd5b and pbd5a)

Full PEX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Zellweger spectrum disorders — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Zellweger syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

PEX2 p.Arg94fs Pathogenic/Likely pathogenic ★★ same condition
PEX2 p.Glu118fs Likely pathogenic ★★ same condition
PEX2 p.Gly113_Arg114insTer Pathogenic/Likely pathogenic ★★ same condition
PEX2 p.Leu204fs Pathogenic/Likely pathogenic ★★ same condition
PEX2 p.Phe263fs Likely pathogenic ★★ same condition
PEX2 p.Cys283fs Likely pathogenic ★ same condition
PEX2 p.Gly149fs Likely pathogenic ★ same condition
PEX2 p.Leu166Ter Pathogenic ★ same residue

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/pex2-p-leu166fs (accessed [today's date]).

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