Is PEX1 p.Gln1192Ter (c.3574C>T) pathogenic?

PEX1 p.Gln1192Ter (c.3574C>T) is classified Pathogenic/Likely pathogenic in PEX1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2024-11-27). Very rare (popmax 0.000339%, nfe); Associated with Heimler syndrome 1.

What condition is associated with PEX1 p.Gln1192Ter (c.3574C>T)?

PEX1 p.Gln1192Ter (c.3574C>T) is associated with Heimler syndrome 1, peroxisome biogenesis disorder 1A (Zellweger), peroxisome biogenesis disorder 1B (ClinVar).

How common is PEX1 p.Gln1192Ter (c.3574C>T) in the general population?

PEX1 p.Gln1192Ter (c.3574C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

PEX1 p.Gln1192Ter

c.3574C>T · rs1057517467 · VCV371698

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

Heimler syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 12	GERP 4.2, phastCons 1
Overall
CADD	40.0	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 0.000339% European (non-Finnish) · 4/1,180,012 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,842 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.Gln1192Ter
Coding: c.3574C>T
MANE Select: NM_021167 · reported on NM_000466
dbSNP: rs1057517467
Type: single nucleotide variant
Location: chr7:92489776 (GRCh38)

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

Disease context

Heimler syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

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-gln1192ter (accessed [today's date]).

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