Is PEX5 p.Arg546= (c.1638C>T) pathogenic?

PEX5 p.Arg546= (c.1638C>T) is classified Conflicting classifications of pathogenicity in PEX5 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-26). Rare (popmax 0.179%, afr); Associated with peroxisome biogenesis disorder 2B.

What condition is associated with PEX5 p.Arg546= (c.1638C>T)?

PEX5 p.Arg546= (c.1638C>T) is associated with peroxisome biogenesis disorder 2B (ClinVar).

How common is PEX5 p.Arg546= (c.1638C>T) in the general population?

PEX5 p.Arg546= (c.1638C>T) is rare (popmax 0.179%, afr) (gnomAD).

PEX5 p.Arg546=

c.1638C>T · rs142408719 · VCV500774

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.179%, afr)

Conditions

peroxisome biogenesis disorder 2B

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.88	GERP -3.6, phastCons 0.003
Overall
CADD	6.407	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.179% African / African-American · 123/68,672 alleles

Filtering AF 0.153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.144%

Overall 0.00912% 145/1,590,776 alleles · rare exomes 62/1,460,402 · genomes 83/130,374 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.179%	558
Admixed American	0.0296%	3,373
Remaining individualsnot grpmax-eligible	0.00484%	20,682
European (non-Finnish)	0.000171%	585,298

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: PEX5
Protein: p.Arg546=
Coding: c.1638C>T
MANE Select: NM_001351132
dbSNP: rs142408719
Type: single nucleotide variant
Location: chr12:7209760 (GRCh38)
Gene constraint: LOEUF 0.768 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.28 · 11 PDB
Residue 546: a UniProt-annotated variant site (in pbd2b; impaired ability to mediate peroxisomal import of proteins containing both a c-terminal pts1- and pts2-type targeting signals); an α-helix

Full PEX5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

peroxisome biogenesis disorder 2B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PEX5 p.Arg546Cys Uncertain significance ★★ ⚠ same residue
PEX5 p.Arg546His Uncertain significance ★ ⚠ same residue
PEX5 c.449-2A>G Pathogenic/Likely pathogenic ★★ same condition
PEX5 c.552-1G>A Pathogenic/Likely pathogenic ★★ same condition
PEX5 c.847-2A>G Likely pathogenic ★★ same condition
PEX5 c.967-1G>A Likely pathogenic ★★ same condition
PEX5 p.Arg237Ter Pathogenic/Likely pathogenic ★★ same condition
PEX5 p.Arg276Ter 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/pex5-p-arg546 (accessed [today's date]).

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