Is PEX26 p.Pro18Leu (c.53C>T) pathogenic?

PEX26 p.Pro18Leu (c.53C>T) is classified Uncertain significance in PEX26 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-24). AlphaMissense: likely benign (0.095); Very rare (popmax 0.00359%, amr); Associated with peroxisome biogenesis disorder 7A (Zellweger).

What condition is associated with PEX26 p.Pro18Leu (c.53C>T)?

PEX26 p.Pro18Leu (c.53C>T) is associated with peroxisome biogenesis disorder 7A (Zellweger), peroxisome biogenesis disorder 7B (ClinVar).

How common is PEX26 p.Pro18Leu (c.53C>T) in the general population?

PEX26 p.Pro18Leu (c.53C>T) is very rare (popmax 0.00359%, amr) (gnomAD).

What do computational predictors say about PEX26 p.Pro18Leu (c.53C>T)?

AlphaMissense predicts likely benign (score 0.095) — an in-silico prediction, not a clinical call.

PEX26 p.Pro18Leu

c.53C>T · rs1295117804 · VCV1518239

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.095 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00359%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

peroxisome biogenesis disorder 7A (Zellweger)

Computational evidence

Protein change
AlphaMissense	0.095	likely benign
REVEL	0.198	benign-leaning
SaProt	LLR -6.06	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.81	GERP 3.7
Regional constraint	o/e 0.98	unconstrained · MANE · 9,695 bp · p 0.72 · regional, not allelic
Overall
CADD	14.79	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00359% Admixed American · 2/55,766 alleles

Filtering AF 0.000595% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000223%

Overall 0.000631% 10/1,585,982 alleles · very rare exomes 10/1,433,806 · genomes 0/152,176 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00359%	27,883
Remaining individualsnot grpmax-eligible	0.00163%	61,420
European (non-Finnish)	0.000598%	167,138

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.Pro18Leu
Coding: c.53C>T
MANE Select: NM_001127649
dbSNP: rs1295117804
Type: single nucleotide variant
Location: chr22:18078429 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.87
Residue 18: the 'disordered' region

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

Disease context

peroxisome biogenesis disorder 7A (Zellweger) — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: peroxisome biogenesis disorder 7B

Similar variants

PEX26 p.Pro18Ser Uncertain significance ★ ⚠ same residue
PEX26 p.Pro18Thr Uncertain significance ★ ⚠ same residue
PEX26 p.Pro18= Likely benign ★ same residue
PEX26 p.Pro18Ala 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

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-pro18leu (accessed [today's date]).

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