Is PEX1 p.Thr215fs (c.643_647del) pathogenic?

PEX1 p.Thr215fs (c.643647del) is classified Pathogenic in PEX1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-05-04). Very rare (popmax 0.00225%, eas); Associated with Zellweger spectrum disorders.

What condition is associated with PEX1 p.Thr215fs (c.643_647del)?

PEX1 p.Thr215fs (c.643_647del) is associated with Zellweger spectrum disorders, peroxisome biogenesis disorder 1A (Zellweger), peroxisome biogenesis disorder 1B (ClinVar).

How common is PEX1 p.Thr215fs (c.643_647del) in the general population?

PEX1 p.Thr215fs (c.643_647del) is very rare (popmax 0.00225%, eas) (gnomAD).

How is Zellweger syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

PEX1 p.Thr215fs

c.643_647del · rs786204544 · VCV188897

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00225%, eas)

Conditions

Zellweger spectrum disorders

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 24
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.5	GERP -3.9, phastCons 0.002
Overall
CADD	23.8	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 0.00225% East Asian · 1/44,448 alleles

Filtering AF 0.000513% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000375%

Overall 0.000778% 12/1,542,060 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00225%	44,448
European (non-Finnish)	0.000956%	104,630

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: PEX1
Protein: p.Thr215fs
Coding: c.643_647del
MANE Select: NM_000466
dbSNP: rs786204544
Type: Deletion
Location: chr7:92517868 (GRCh38)
Gene constraint: LOEUF 0.746 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.19

Full PEX1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Zellweger spectrum disorders — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: peroxisome biogenesis disorder 1A (Zellweger)peroxisome biogenesis disorder 1B peroxisome biogenesis disorder

For Zellweger syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

PEX1 p.Thr215= Likely benign ★ same residue
PEX1 c.2072-42_2085del Likely pathogenic ★★ same condition
PEX1 p.Ala15fs Pathogenic/Likely pathogenic ★★ same condition
PEX1 p.Ala921fs Pathogenic/Likely pathogenic ★★ same condition
PEX1 p.Arg1208fs Pathogenic/Likely pathogenic ★★ same condition
PEX1 p.Arg827fs Pathogenic ★★ same condition
PEX1 p.Asn1088fs Pathogenic/Likely pathogenic ★★ same condition
PEX1 p.Asn403fs 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/pex1-p-thr215fs (accessed [today's date]).

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