Is PEX1 p.Arg1275Ter (c.3823C>T) pathogenic?

PEX1 p.Arg1275Ter (c.3823C>T) is classified Uncertain significance in PEX1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2022-08-15). Very rare (popmax 0.00169%, amr); Associated with Zellweger spectrum disorders.

What condition is associated with PEX1 p.Arg1275Ter (c.3823C>T)?

PEX1 p.Arg1275Ter (c.3823C>T) is associated with Zellweger spectrum disorders, peroxisome biogenesis disorder 1A (Zellweger) (ClinVar).

How common is PEX1 p.Arg1275Ter (c.3823C>T) in the general population?

PEX1 p.Arg1275Ter (c.3823C>T) is very rare (popmax 0.00169%, amr) (gnomAD).

How is Zellweger syndrome inherited?

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

PEX1 p.Arg1275Ter

c.3823C>T · rs755549316 · VCV555569

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00169%, amr)

Conditions

Zellweger spectrum disorders

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 7.3	GERP 3.9, phastCons 1
Overall
CADD	41.0	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 0.00169% Admixed American · 1/59,298 alleles

Filtering AF 0.000185% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000122%

Overall 0.000502% 8/1,594,348 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00169%	59,298
African / African-American	0.00134%	74,512
European (non-Finnish)	0.000515%	194,195

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.Arg1275Ter
Coding: c.3823C>T
MANE Select: NM_021167 · reported on NM_000466
dbSNP: rs755549316
Type: single nucleotide variant
Location: chr7:92487486 (GRCh38)

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)

For Zellweger syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

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-arg1275ter (accessed [today's date]).

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