Is PEX2 p.Phe163Cys (c.488T>G) pathogenic?

PEX2 p.Phe163Cys (c.488T>G) is classified Uncertain significance in PEX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-07). AlphaMissense: ambiguous (0.4565); Very rare (popmax 0.00364%, nfe); Associated with peroxisome biogenesis disorder 5A (Zellweger).

What condition is associated with PEX2 p.Phe163Cys (c.488T>G)?

PEX2 p.Phe163Cys (c.488T>G) is associated with peroxisome biogenesis disorder 5A (Zellweger) (ClinVar).

How common is PEX2 p.Phe163Cys (c.488T>G) in the general population?

PEX2 p.Phe163Cys (c.488T>G) is very rare (popmax 0.00364%, nfe) (gnomAD).

What do computational predictors say about PEX2 p.Phe163Cys (c.488T>G)?

AlphaMissense predicts ambiguous (score 0.4565) — an in-silico prediction, not a clinical call.

PEX2 p.Phe163Cys

c.488T>G · rs781502702 · VCV2147228

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4565 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00364%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

peroxisome biogenesis disorder 5A (Zellweger)

Computational evidence

Protein change
AlphaMissense	0.4565	ambiguous
REVEL	0.859	moderately pathogenic-leaning
SaProt	LLR -6.83	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 914 bp · p 0.85 · regional, not allelic
Overall
CADD	26.4	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

Grpmax group 0.00364% European (non-Finnish) · 43/1,180,040 alleles

Filtering AF 0.00275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00244%

Overall 0.00366% 59/1,614,042 alleles · very rare exomes 55/1,461,822 · genomes 4/152,220 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0188%	5,332
Remaining individualsnot grpmax-eligible	0.0064%	15,622
European (non-Finnish)grpmax	0.00364%	27,443

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe163Cys
Coding: c.488T>G
MANE Select: NM_000318
dbSNP: rs781502702
Type: single nucleotide variant
Location: chr8:76983691 (GRCh38)
Gene constraint: LOEUF 1.057 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.17
Residue 163: 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

peroxisome biogenesis disorder 5A (Zellweger) — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PEX2 p.Phe163= Likely benign ★ same residue
PEX2 p.Phe163fs Likely pathogenic ★ same residue
PEX2 c.-17-2A>G Pathogenic/Likely pathogenic ★★ same condition
PEX2 p.Arg119Ter Pathogenic ★★ same condition
PEX2 p.Arg125Ter Pathogenic/Likely pathogenic ★★ same condition
PEX2 p.Gln31Ter Pathogenic/Likely pathogenic ★★ same condition
PEX2 p.Gln78Ter Pathogenic/Likely pathogenic ★★ same condition
PEX2 p.Gln96Ter 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/pex2-p-phe163cys (accessed [today's date]).

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