Is PEX13 p.Ala223= (c.669T>C) pathogenic?

PEX13 p.Ala223= (c.669T>C) is classified Likely benign in PEX13 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-23). Very rare (popmax 8.48e-05%, nfe); Associated with peroxisome biogenesis disorder 11A (Zellweger).

What condition is associated with PEX13 p.Ala223= (c.669T>C)?

PEX13 p.Ala223= (c.669T>C) is associated with peroxisome biogenesis disorder 11A (Zellweger) (ClinVar).

How common is PEX13 p.Ala223= (c.669T>C) in the general population?

PEX13 p.Ala223= (c.669T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

PEX13 p.Ala223=

c.669T>C · rs1680459954 · VCV2127087

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

peroxisome biogenesis disorder 11A (Zellweger)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.5	GERP -3.3
Overall
CADD	0.522	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,820 alleles

Overall 0.000124% 2/1,613,914 alleles · very rare exomes 2/1,461,598 · genomes 0/152,316 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	64,024
European (non-Finnish)grpmax	8.48e-05%	1,179,820

Finnish 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: PEX13
Protein: p.Ala223=
Coding: c.669T>C
MANE Select: NM_002618
dbSNP: rs1680459954
Type: single nucleotide variant
Location: chr2:61031995 (GRCh38)
Gene constraint: LOEUF 1.159 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.62 · 3 PDB
Residue 223: the 'targeting to peroxisomes' region

Full PEX13 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

peroxisome biogenesis disorder 11A (Zellweger) — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PEX13 p.Arg16Ter Pathogenic/Likely pathogenic ★★ same condition
PEX13 p.Arg170Ter Pathogenic/Likely pathogenic ★★ same condition
PEX13 p.Arg226Ter Pathogenic ★★ same condition
PEX13 p.Gln131Ter Pathogenic ★★ same condition
PEX13 p.Glu123Ter Pathogenic ★★ same condition
PEX13 p.Tyr155Ter Pathogenic/Likely pathogenic ★★ same condition
PEX13 c.913+3A>G Uncertain significance ★★ same condition
PEX13 p.Ala302Gly Uncertain significance ★★ 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/pex13-p-ala223 (accessed [today's date]).

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