Is PEX2 p.Ser18Arg (c.54C>A) pathogenic?

PEX2 p.Ser18Arg (c.54C>A) is classified Uncertain significance in PEX2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-08-14). AlphaMissense: likely pathogenic (0.7649); Very rare (popmax 0.00223%, eas); Associated with Zellweger spectrum disorders.

What condition is associated with PEX2 p.Ser18Arg (c.54C>A)?

PEX2 p.Ser18Arg (c.54C>A) is associated with Zellweger spectrum disorders (ClinVar).

How common is PEX2 p.Ser18Arg (c.54C>A) in the general population?

PEX2 p.Ser18Arg (c.54C>A) is very rare (popmax 0.00223%, eas) (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.Ser18Arg (c.54C>A)?

AlphaMissense predicts likely pathogenic (score 0.7649) — an in-silico prediction, not a clinical call.

PEX2 p.Ser18Arg

c.54C>A · rs545785018 · VCV991600

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7649 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Zellweger spectrum disorders

Computational evidence

Protein change
AlphaMissense	0.7649	likely pathogenic · top 9% in PEX2
REVEL	0.312	indeterminate
SaProt	LLR -11.25	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP -1.2, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 914 bp · p 0.85 · regional, not allelic
Overall
CADD	19.97	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,878 alleles

Overall 6.2e-05% 1/1,613,902 alleles · very rare exomes 0/1,461,690 · genomes 1/152,212 · 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.Ser18Arg
Coding: c.54C>A
MANE Select: NM_000318
dbSNP: rs545785018
Type: single nucleotide variant
Location: chr8:76984125 (GRCh38)
Gene constraint: LOEUF 1.057 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.17

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.Ser18Asn Uncertain significance ⚠ same residue
PEX2 p.Ser18= Likely benign ★ same residue
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

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-ser18arg (accessed [today's date]).

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