Is PEX1 p.Ile1200Phe (c.3598A>T) pathogenic?

PEX1 p.Ile1200Phe (c.3598A>T) is classified Uncertain significance in PEX1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-05-27). AlphaMissense: likely benign (0.2157); Very rare (popmax 0.000169%, nfe); Associated with Zellweger spectrum disorders.

What condition is associated with PEX1 p.Ile1200Phe (c.3598A>T)?

PEX1 p.Ile1200Phe (c.3598A>T) is associated with Zellweger spectrum disorders (ClinVar).

How common is PEX1 p.Ile1200Phe (c.3598A>T) in the general population?

PEX1 p.Ile1200Phe (c.3598A>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

How is Zellweger syndrome inherited?

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

What do computational predictors say about PEX1 p.Ile1200Phe (c.3598A>T)?

AlphaMissense predicts likely benign (score 0.2157) — an in-silico prediction, not a clinical call.

PEX1 p.Ile1200Phe

c.3598A>T · rs886043722 · VCV287772

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2157 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Zellweger spectrum disorders

Computational evidence

Protein change
AlphaMissense	0.2157	likely benign
REVEL	0.61	indeterminate
SaProt	LLR -8.32	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 2.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 41 kb · p 4.3e-05 · regional, not allelic
Overall
CADD	21.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,000 alleles

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

Overall 0.000137% 2/1,461,834 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.Ile1200Phe
Coding: c.3598A>T
MANE Select: NM_021167 · reported on NM_000466
dbSNP: rs886043722
Type: single nucleotide variant
Location: chr7:92489752 (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

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-ile1200phe (accessed [today's date]).

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