Is PEX5 p.Arg593Trp (c.1777C>T) pathogenic?

PEX5 p.Arg593Trp (c.1777C>T) is classified Uncertain significance in PEX5 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-08). AlphaMissense: likely benign (0.141); Very rare (popmax 0.00801%, afr); Associated with peroxisome biogenesis disorder 2B.

What condition is associated with PEX5 p.Arg593Trp (c.1777C>T)?

PEX5 p.Arg593Trp (c.1777C>T) is associated with peroxisome biogenesis disorder 2B (ClinVar).

How common is PEX5 p.Arg593Trp (c.1777C>T) in the general population?

PEX5 p.Arg593Trp (c.1777C>T) is very rare (popmax 0.00801%, afr) (gnomAD).

What do computational predictors say about PEX5 p.Arg593Trp (c.1777C>T)?

AlphaMissense predicts likely benign (score 0.141) — an in-silico prediction, not a clinical call.

PEX5 p.Arg593Trp

c.1777C>T · rs144333076 · VCV843623

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.141 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

peroxisome biogenesis disorder 2B

Computational evidence

Protein change
AlphaMissense	0.141	likely benign
REVEL	0.618	indeterminate
SaProt	LLR -10.19	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 1.6, phastCons 1
Overall
CADD	27.5	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 0.00801% African / African-American · 6/74,930 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00228%

Overall 0.00223% 36/1,614,110 alleles · very rare exomes 29/1,461,892 · genomes 7/152,218 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00801%	12,488
Admixed American	0.005%	20,001
European (non-Finnish)	0.00212%	47,202
Remaining individualsnot grpmax-eligible	0.0016%	62,488
Finnishnot grpmax-eligible	0.00156%	64,046

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.Arg593Trp
Coding: c.1777C>T
MANE Select: NM_001351132
dbSNP: rs144333076
Type: single nucleotide variant
Location: chr12:7210080 (GRCh38)
Gene constraint: LOEUF 0.768 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.28 · 11 PDB
Residue 593: 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); a β-strand

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.Arg593Pro Uncertain significance ★ ⚠ same residue
PEX5 p.Arg593= Likely benign ★ same residue
PEX5 p.Arg593Gln 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

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-arg593trp (accessed [today's date]).

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