Is PEX1 p.Glu376fs (c.1126del) pathogenic?

PEX1 p.Glu376fs (c.1126del) is classified Pathogenic/Likely pathogenic in PEX1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-03-13). Very rare (popmax 0.00333%, amr); Associated with peroxisome biogenesis disorder 1A (Zellweger).

What condition is associated with PEX1 p.Glu376fs (c.1126del)?

PEX1 p.Glu376fs (c.1126del) is associated with peroxisome biogenesis disorder 1A (Zellweger), peroxisome biogenesis disorder 1B, peroxisome biogenesis disorder (ClinVar).

How common is PEX1 p.Glu376fs (c.1126del) in the general population?

PEX1 p.Glu376fs (c.1126del) is very rare (popmax 0.00333%, amr) (gnomAD).

PEX1 p.Glu376fs

c.1126del · rs751829426 · VCV813450

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

peroxisome biogenesis disorder 1A (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	predicted	premature termination codon in exon 5 of 24
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.4	GERP 3.1, phastCons 0.99

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,004 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000137% 2/1,461,696 alleles · very rare

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.Glu376fs
Coding: c.1126del
MANE Select: NM_000466
dbSNP: rs751829426
Type: Deletion
Location: chr7:92517389 (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

peroxisome biogenesis disorder 1A (Zellweger) — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: peroxisome biogenesis disorder 1B peroxisome biogenesis disorder Zellweger spectrum disorders

Similar variants

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
PEX1 p.Asp378fs 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/pex1-p-glu376fs (accessed [today's date]).

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