Is PEX26 p.Pro117Ser (c.349C>T) pathogenic?

PEX26 p.Pro117Ser (c.349C>T) is classified Uncertain significance in PEX26 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-17). AlphaMissense: likely pathogenic (0.7302); Very rare (popmax 0.00133%, afr).

How common is PEX26 p.Pro117Ser (c.349C>T) in the general population?

PEX26 p.Pro117Ser (c.349C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about PEX26 p.Pro117Ser (c.349C>T)?

AlphaMissense predicts likely pathogenic (score 0.7302) — an in-silico prediction, not a clinical call.

PEX26 p.Pro117Ser

c.349C>T · VCV3896212

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7302 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7302	likely pathogenic · top 9% in PEX26
REVEL	0.91	moderately pathogenic-leaning
SaProt	LLR -9.03	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 4.3, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 9,695 bp · p 0.72 · regional, not allelic
Overall
CADD	26.9	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 0.00133% African / African-American · 1/75,024 alleles

Overall 0.000137% 2/1,461,824 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,506
African / African-Americangrpmax	0.00133%	75,024

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: PEX26
Protein: p.Pro117Ser
Coding: c.349C>T
MANE Select: NM_001127649
Type: single nucleotide variant
Location: chr22:18079992 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.87
Residue 117: a UniProt-annotated variant site (in pbd-cg8; impaired protein import into peroxisome; decreased interaction with pex6; does not affect localization to peroxisomal membrane)

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

Similar variants

PEX26 p.Pro117Thr Likely pathogenic ★ ⚠ same residue
PEX26 p.Pro117Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
PEX26 p.Pro117= Likely benign ★ same residue
PEX26 c.230+1G>T Pathogenic ★★ same type
PEX26 c.667+2T>C Pathogenic/Likely pathogenic ★★ same type
PEX26 p.Arg192Ter Pathogenic/Likely pathogenic ★★ same type
PEX26 p.Arg98Trp Pathogenic/Likely pathogenic ★★ same type
PEX26 p.Gln146Ter Pathogenic ★★ same type

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-pro117ser (accessed [today's date]).

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