Is PEX26 p.Arg166Trp (c.496C>T) pathogenic?

PEX26 p.Arg166Trp (c.496C>T) is classified Uncertain significance in PEX26 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-07-30). AlphaMissense: likely benign (0.1435); Ultra-rare (popmax 0.0103%, nfe); Associated with peroxisome biogenesis disorder 7B.

What condition is associated with PEX26 p.Arg166Trp (c.496C>T)?

PEX26 p.Arg166Trp (c.496C>T) is associated with peroxisome biogenesis disorder 7B, peroxisome biogenesis disorder 7A (Zellweger) (ClinVar).

How common is PEX26 p.Arg166Trp (c.496C>T) in the general population?

PEX26 p.Arg166Trp (c.496C>T) is ultra-rare (popmax 0.0103%, nfe) (gnomAD).

What do computational predictors say about PEX26 p.Arg166Trp (c.496C>T)?

AlphaMissense predicts likely benign (score 0.1435) — an in-silico prediction, not a clinical call.

PEX26 p.Arg166Trp

c.496C>T · rs369695924 · VCV501434

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1435 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0103%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

peroxisome biogenesis disorder 7B

Computational evidence

Protein change
AlphaMissense	0.1435	likely benign
REVEL	0.564	indeterminate
SaProt	LLR -7.95	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 4.1, phastCons 0.09
Regional constraint	o/e 0.98	unconstrained · MANE · 9,695 bp · p 0.72 · regional, not allelic
Overall
CADD	25.1	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 0.0103% European (non-Finnish) · 121/1,179,928 alleles

Filtering AF 0.00876% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0082%

Overall 0.00818% 132/1,613,912 alleles · ultra-rare exomes 124/1,461,756 · genomes 8/152,156 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0103%	9,751
Admixed American	0.00833%	11,998
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
East Asian	0.00223%	44,896
South Asian	0.0022%	45,541
Remaining individualsnot grpmax-eligible	0.0016%	62,480
African / African-American	0.00133%	74,914

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.Arg166Trp
Coding: c.496C>T
MANE Select: NM_001127649
dbSNP: rs369695924
Type: single nucleotide variant
Location: chr22:18083561 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.87

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

Disease context

peroxisome biogenesis disorder 7B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: peroxisome biogenesis disorder 7A (Zellweger)

Similar variants

PEX26 p.Arg166Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
PEX26 p.Arg166= 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

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-arg166trp (accessed [today's date]).

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