Is PEX12 p.Pro215fs (c.644del) pathogenic?

PEX12 p.Pro215fs (c.644del) is classified Pathogenic in PEX12 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-05-08). Very rare (popmax 0.00167%, amr); Associated with peroxisome biogenesis disorder 3A (Zellweger).

What condition is associated with PEX12 p.Pro215fs (c.644del)?

PEX12 p.Pro215fs (c.644del) is associated with peroxisome biogenesis disorder 3A (Zellweger), peroxisome biogenesis disorder type 3B (ClinVar).

How common is PEX12 p.Pro215fs (c.644del) in the general population?

PEX12 p.Pro215fs (c.644del) is very rare (popmax 0.00167%, amr) (gnomAD).

PEX12 p.Pro215fs

c.644del · rs1199283977 · VCV556886

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

peroxisome biogenesis disorder 3A (Zellweger)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (2 of 3, 36 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.1
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,998 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,614,074 alleles · very rare exomes 2/1,461,882 · genomes 1/152,192 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,998
European (non-Finnish)	0.000169%	590,019

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: PEX12
Protein: p.Pro215fs
Coding: c.644del
MANE Select: NM_000286
dbSNP: rs1199283977
Type: Deletion
Location: chr17:35577074 (GRCh38)
Gene constraint: LOEUF 1.218 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.58

Full PEX12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

peroxisome biogenesis disorder 3A (Zellweger) — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: peroxisome biogenesis disorder type 3B

Similar variants

PEX12 p.Pro215= Likely benign ★ same residue
PEX12 p.Gln17fs Pathogenic/Likely pathogenic ★★ same condition
PEX12 p.Gln270fs Pathogenic/Likely pathogenic ★★ same condition
PEX12 p.Glu171fs Pathogenic/Likely pathogenic ★★ same condition
PEX12 p.Gly321fs Pathogenic/Likely pathogenic ★★ same condition
PEX12 p.Leu296fs Pathogenic ★★ same condition
PEX12 p.Lys299_Met300insTer Pathogenic/Likely pathogenic ★★ same condition
PEX12 p.Ser229fs 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/pex12-p-pro215fs (accessed [today's date]).

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