Is PEX5 p.Ser464Phe (c.1391C>T) pathogenic?

PEX5 p.Ser464Phe (c.1391C>T) is classified Uncertain significance in PEX5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-18). AlphaMissense: likely pathogenic (0.6123); Very rare (popmax 8.5e-05%, nfe); Associated with peroxisome biogenesis disorder 2B.

What condition is associated with PEX5 p.Ser464Phe (c.1391C>T)?

PEX5 p.Ser464Phe (c.1391C>T) is associated with peroxisome biogenesis disorder 2B (ClinVar).

How common is PEX5 p.Ser464Phe (c.1391C>T) in the general population?

PEX5 p.Ser464Phe (c.1391C>T) is very rare (popmax 8.5e-05%, nfe) (gnomAD).

What do computational predictors say about PEX5 p.Ser464Phe (c.1391C>T)?

AlphaMissense predicts likely pathogenic (score 0.6123) — an in-silico prediction, not a clinical call.

PEX5 p.Ser464Phe

c.1391C>T · rs1945132114 · VCV2122008

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6123 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.5e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

peroxisome biogenesis disorder 2B

Computational evidence

Protein change
AlphaMissense	0.6123	likely pathogenic
REVEL	0.469	indeterminate
SaProt	LLR -8.87	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.80 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.8	GERP 0.52, phastCons 1
Overall
CADD	24.1	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 8.5e-05% European (non-Finnish) · 1/1,177,098 alleles

Overall 6.21e-05% 1/1,610,598 alleles · very rare exomes 0/1,458,476 · genomes 1/152,122 · joint denominator

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.Ser464Phe
Coding: c.1391C>T
MANE Select: NM_001351132
dbSNP: rs1945132114
Type: single nucleotide variant
Location: chr12:7208666 (GRCh38)
Gene constraint: LOEUF 0.768 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.28 · 11 PDB
Residue 464: 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.Ser464= Likely benign ★ 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
PEX5 p.Arg420Ter 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-ser464phe (accessed [today's date]).

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