Is PEX26 p.Leu45Pro (c.134T>C) pathogenic?

PEX26 p.Leu45Pro (c.134T>C) is classified Conflicting classifications of pathogenicity in PEX26 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2024-06-19). AlphaMissense: likely pathogenic (0.9386); Very rare (popmax 0.000947%, nfe); Associated with PEX26-related disorder.

What condition is associated with PEX26 p.Leu45Pro (c.134T>C)?

PEX26 p.Leu45Pro (c.134T>C) is associated with PEX26-related disorder, peroxisome biogenesis disorder 7A (Zellweger), peroxisome biogenesis disorder 7B (ClinVar).

How common is PEX26 p.Leu45Pro (c.134T>C) in the general population?

PEX26 p.Leu45Pro (c.134T>C) is very rare (popmax 0.000947%, nfe) (gnomAD).

What do computational predictors say about PEX26 p.Leu45Pro (c.134T>C)?

AlphaMissense predicts likely pathogenic (score 0.9386) — an in-silico prediction, not a clinical call.

PEX26 p.Leu45Pro

c.134T>C · rs61752132 · VCV2157

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9386 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000947%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PEX26-related disorder

Computational evidence

Protein change
AlphaMissense	0.9386	likely pathogenic · top 2% in PEX26
REVEL	0.726	pathogenic-leaning
SaProt	LLR -14.45	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 3.5, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 9,695 bp · p 0.72 · regional, not allelic
Overall
CADD	32.0	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 0.000947% European (non-Finnish) · 11/1,161,952 alleles

Filtering AF 0.000508% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000371%

Overall 0.000775% 11/1,419,736 alleles · very rare

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: PEX26
Protein: p.Leu45Pro
Coding: c.134T>C
MANE Select: NM_001127649
dbSNP: rs61752132
Type: single nucleotide variant
Location: chr22:18078510 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.87
Residue 45: a UniProt-annotated variant site (in pbd7b; infantile refsum disease)

Full PEX26 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

PEX26-related disorder

Also linked: peroxisome biogenesis disorder 7A (Zellweger)peroxisome biogenesis disorder 7B peroxisome biogenesis disorder

Similar variants

PEX26 p.Leu45= Likely benign ★ same residue
PEX26 c.230+1G>T Pathogenic ★★ same condition
PEX26 c.667+2T>C Pathogenic/Likely pathogenic ★★ same condition
PEX26 p.Arg192Ter Pathogenic/Likely pathogenic ★★ same condition
PEX26 p.Arg98Trp Pathogenic/Likely pathogenic ★★ same condition
PEX26 p.Gln146Ter Pathogenic ★★ same condition
PEX26 p.Gly89Arg Pathogenic/Likely pathogenic ★★ ⚠ same condition
PEX26 p.Trp62Ter 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/pex26-p-leu45pro (accessed [today's date]).

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