Is PEX5 p.Phe99Leu (c.297C>A) pathogenic?

PEX5 p.Phe99Leu (c.297C>A) is classified Uncertain significance in PEX5 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-06-29). AlphaMissense: likely pathogenic (0.6197); Ultra-rare (popmax 0.0262%, nfe); Associated with peroxisome biogenesis disorder 2B.

What condition is associated with PEX5 p.Phe99Leu (c.297C>A)?

PEX5 p.Phe99Leu (c.297C>A) is associated with peroxisome biogenesis disorder 2B (ClinVar).

How common is PEX5 p.Phe99Leu (c.297C>A) in the general population?

PEX5 p.Phe99Leu (c.297C>A) is ultra-rare (popmax 0.0262%, nfe) (gnomAD).

What do computational predictors say about PEX5 p.Phe99Leu (c.297C>A)?

AlphaMissense predicts likely pathogenic (score 0.6197) — an in-silico prediction, not a clinical call.

PEX5 p.Phe99Leu

c.297C>A · rs573650362 · VCV598498

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.6197 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0262%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

peroxisome biogenesis disorder 2B

Computational evidence

Protein change
AlphaMissense	0.6197	likely pathogenic
REVEL	0.23	benign-leaning
SaProt	LLR -4.44	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.21	GERP -2.8, phastCons 0.29
Overall
CADD	16.39	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 0.0262% European (non-Finnish) · 309/1,180,036 alleles

Filtering AF 0.0237% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0228%

Overall 0.0194% 313/1,614,050 alleles · ultra-rare exomes 308/1,461,884 · genomes 5/152,166 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0262%	3,819
Remaining individualsnot grpmax-eligible	0.0064%	15,622

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.Phe99Leu
Coding: c.297C>A
MANE Select: NM_001351132
dbSNP: rs573650362
Type: single nucleotide variant
Location: chr12:7191339 (GRCh38)
Gene constraint: LOEUF 0.768 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.28 · 11 PDB
Residue 99: the 'amphipathic helix 2 (ah2)' region

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.Phe99= 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-phe99leu (accessed [today's date]).

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