Is PEX5 p.Phe218= (c.654C>T) pathogenic?

PEX5 p.Phe218= (c.654C>T) is classified Likely benign in PEX5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-15). Very rare (popmax 0.00446%, eas); Associated with peroxisome biogenesis disorder 2B.

What condition is associated with PEX5 p.Phe218= (c.654C>T)?

PEX5 p.Phe218= (c.654C>T) is associated with peroxisome biogenesis disorder 2B (ClinVar).

How common is PEX5 p.Phe218= (c.654C>T) in the general population?

PEX5 p.Phe218= (c.654C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

PEX5 p.Phe218=

c.654C>T · rs752935710 · VCV1588721

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

peroxisome biogenesis disorder 2B

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.8	GERP 1.7, phastCons 1
Overall
CADD	14.77	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,872 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00124% 20/1,614,036 alleles · very rare exomes 19/1,461,860 · genomes 1/152,176 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,436
African / African-American	0.00267%	37,500
European (non-Finnish)	0.00127%	78,668
South Asian	0.0011%	91,064

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.Phe218=
Coding: c.654C>T
MANE Select: NM_001351132
dbSNP: rs752935710
Type: single nucleotide variant
Location: chr12:7202252 (GRCh38)
Gene constraint: LOEUF 0.768 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.28 · 11 PDB
Residue 218: a UniProt-annotated variant site (found in a family with congenital cataract; likely pathogenic; impaired interaction with pex7; impaired ability to mediate peroxisomal import of proteins containing a c-terminal pts2-type targeting signal without affecting import of proteins with a pts1 targeting signal)

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.Phe218Leu Uncertain significance ★ ⚠ same residue
PEX5 p.Phe218Ser Pathogenic ★ 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-phe218 (accessed [today's date]).

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