Is PEX2 p.His261Arg (c.782A>G) pathogenic?

PEX2 p.His261Arg (c.782A>G) is classified Conflicting classifications of pathogenicity in PEX2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-12-16). AlphaMissense: likely pathogenic (0.809); Very rare (popmax 0.00833%, amr); Associated with Zellweger spectrum disorders.

What condition is associated with PEX2 p.His261Arg (c.782A>G)?

PEX2 p.His261Arg (c.782A>G) is associated with Zellweger spectrum disorders, peroxisome biogenesis disorder 5A (Zellweger), peroxisome biogenesis disorder 5B (ClinVar).

How common is PEX2 p.His261Arg (c.782A>G) in the general population?

PEX2 p.His261Arg (c.782A>G) is very rare (popmax 0.00833%, amr) (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.His261Arg (c.782A>G)?

AlphaMissense predicts likely pathogenic (score 0.809) — an in-silico prediction, not a clinical call.

PEX2 p.His261Arg

c.782A>G · rs749956542 · VCV557949

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.809 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Zellweger spectrum disorders

Computational evidence

Protein change
AlphaMissense	0.809	likely pathogenic · top 7% in PEX2
REVEL	0.96	strongly pathogenic-leaning
SaProt	LLR -14.47	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 914 bp · p 0.85 · regional, not allelic
Overall
CADD	26.3	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 0.00833% Admixed American · 5/60,002 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000744% 12/1,613,966 alleles · very rare exomes 10/1,461,798 · genomes 2/152,168 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,000
Remaining individualsnot grpmax-eligible	0.0032%	31,244
European (non-Finnish)	0.000424%	236,003

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.His261Arg
Coding: c.782A>G
MANE Select: NM_000318
dbSNP: rs749956542
Type: single nucleotide variant
Location: chr8:76983397 (GRCh38)
Gene constraint: LOEUF 1.057 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.17
Residue 261: 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

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

For Zellweger syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

PEX2 p.His261= Likely benign ★ 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-his261arg (accessed [today's date]).

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