Is PEX2 p.Trp250Arg (c.748T>C) pathogenic?

PEX2 p.Trp250Arg (c.748T>C) is classified Conflicting classifications of pathogenicity in PEX2 (ClinVar, Conflicting submitters, 14 submitters; last evaluated 2026-04-01). AlphaMissense: likely pathogenic (0.7962); Low-frequency (popmax 1.18%, nfe); Associated with peroxisome biogenesis disorder 5A (Zellweger).

What condition is associated with PEX2 p.Trp250Arg (c.748T>C)?

PEX2 p.Trp250Arg (c.748T>C) is associated with peroxisome biogenesis disorder 5A (Zellweger), peroxisome biogenesis disorder 1A (Zellweger), peroxisome biogenesis disorder 5B (ClinVar).

How common is PEX2 p.Trp250Arg (c.748T>C) in the general population?

PEX2 p.Trp250Arg (c.748T>C) is low-frequency (popmax 1.18%, nfe) (gnomAD).

What do computational predictors say about PEX2 p.Trp250Arg (c.748T>C)?

AlphaMissense predicts likely pathogenic (score 0.7962) — an in-silico prediction, not a clinical call.

PEX2 p.Trp250Arg

c.748T>C · rs142645936 · VCV129885

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 14 submitters

AlphaMissense

likely pathogenic

0.7962 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.18%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

peroxisome biogenesis disorder 5A (Zellweger)

Computational evidence

Protein change
AlphaMissense	0.7962	likely pathogenic · top 8% in PEX2
REVEL	0.55	indeterminate
SaProt	LLR -1.70	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL 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	27.0	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 1.18% European (non-Finnish) · 13,894/1,180,008 alleles

Filtering AF 1.16% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.15%

Overall 0.941% 15,181/1,614,098 alleles · low-frequency exomes 14,320/1,461,854 · genomes 861/152,244 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	1.18%	85
Remaining individualsnot grpmax-eligible	0.885%	113
Ashkenazi Jewishnot grpmax-eligible	0.503%	199
Finnishnot grpmax-eligible	0.245%	408
South Asian	0.194%	515
Admixed American	0.187%	536
African / African-American	0.169%	591
Middle Eastern	0.165%	606
East Asian	0.00446%	22,435

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.Trp250Arg
Coding: c.748T>C
MANE Select: NM_000318
dbSNP: rs142645936
Type: single nucleotide variant
Location: chr8:76983431 (GRCh38)
Gene constraint: LOEUF 1.057 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.17
Residue 250: 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

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

Also linked: peroxisome biogenesis disorder 1A (Zellweger)peroxisome biogenesis disorder 5B Zellweger spectrum disorders

Similar variants

PEX2 p.Trp250Gly Uncertain significance ★ ⚠ 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
PEX2 p.Glu168Ter Pathogenic/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/pex2-p-trp250arg (accessed [today's date]).

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