Is PEX2 p.Cys280Ser (c.839G>C) pathogenic?

PEX2 p.Cys280Ser (c.839G>C) is classified Uncertain significance in PEX2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-01-21). AlphaMissense: likely pathogenic (0.9203); Absent from gnomAD v4.1; Associated with Zellweger spectrum disorders.

What condition is associated with PEX2 p.Cys280Ser (c.839G>C)?

PEX2 p.Cys280Ser (c.839G>C) is associated with Zellweger spectrum disorders (ClinVar).

How common is PEX2 p.Cys280Ser (c.839G>C) in the general population?

PEX2 p.Cys280Ser (c.839G>C) is absent from gnomAD v4.1 (gnomAD).

How is Zellweger syndrome inherited?

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

What do computational predictors say about PEX2 p.Cys280Ser (c.839G>C)?

AlphaMissense predicts likely pathogenic (score 0.9203) — an in-silico prediction, not a clinical call.

PEX2 p.Cys280Ser

c.839G>C · VCV4059629

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9203 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Zellweger spectrum disorders

Computational evidence

Protein change
AlphaMissense	0.9203	likely pathogenic · top 2% in PEX2
REVEL	0.964	strongly pathogenic-leaning
SaProt	LLR -9.19	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 914 bp · p 0.85 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PEX2
Protein: p.Cys280Ser
Coding: c.839G>C
MANE Select: NM_000318
Type: single nucleotide variant
Location: chr8:76983340 (GRCh38)
Gene constraint: LOEUF 1.057 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.17
Residue 280: a binding site; a UniProt-annotated variant site (in pbd5a); a UniProt-annotated variant site (in pbd5b and pbd5a); a UniProt-annotated variant site (in pbd5b)

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.Arg119Ter Pathogenic ★★ same condition
PEX2 p.Arg125Ter Pathogenic/Likely pathogenic ★★ same condition
PEX2 p.Gln31Ter Pathogenic/Likely pathogenic ★★ same condition
PEX2 p.Trp105Ter Pathogenic/Likely pathogenic ★★ same condition
PEX2 p.Ala8Val Uncertain significance ★★ ⚠ same condition
PEX2 p.Arg125Gln Uncertain significance ★★ ⚠ same condition
PEX2 p.Arg51His Uncertain significance ★★ ⚠ same condition
PEX2 p.Cys184Tyr 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/pex2-p-cys280ser (accessed [today's date]).

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