Is PEX5 p.Pro366Leu (c.1097C>T) pathogenic?

PEX5 p.Pro366Leu (c.1097C>T) is classified Uncertain significance in PEX5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-02). AlphaMissense: likely benign (0.208); Very rare (popmax 0.00169%, nfe); Associated with peroxisome biogenesis disorder 2B.

What condition is associated with PEX5 p.Pro366Leu (c.1097C>T)?

PEX5 p.Pro366Leu (c.1097C>T) is associated with peroxisome biogenesis disorder 2B (ClinVar).

How common is PEX5 p.Pro366Leu (c.1097C>T) in the general population?

PEX5 p.Pro366Leu (c.1097C>T) is very rare (popmax 0.00169%, nfe) (gnomAD).

What do computational predictors say about PEX5 p.Pro366Leu (c.1097C>T)?

AlphaMissense predicts likely benign (score 0.208) — an in-silico prediction, not a clinical call.

PEX5 p.Pro366Leu

c.1097C>T · rs764934631 · VCV959865

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.208 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00169%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

peroxisome biogenesis disorder 2B

Computational evidence

Protein change
AlphaMissense	0.208	likely benign
REVEL	0.731	pathogenic-leaning
SaProt	LLR -11.66	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.8	GERP 1.8, phastCons 1
Overall
CADD	27.4	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 0.00169% European (non-Finnish) · 20/1,180,008 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00161% 26/1,614,008 alleles · very rare exomes 25/1,461,850 · genomes 1/152,158 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0064%	15,620
European (non-Finnish)grpmax	0.00169%	59,001
African / African-American	0.00133%	74,922
South Asian	0.0011%	91,080

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro366Leu
Coding: c.1097C>T
MANE Select: NM_001351132
dbSNP: rs764934631
Type: single nucleotide variant
Location: chr12:7207789 (GRCh38)
Gene constraint: LOEUF 0.768 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.28 · 11 PDB

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

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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
PEX5 p.Arg427Ter 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-pro366leu (accessed [today's date]).

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