Is PEX1 p.Leu522Phe (c.1566G>C) pathogenic?

PEX1 p.Leu522Phe (c.1566G>C) is classified Conflicting classifications of pathogenicity in PEX1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-17). AlphaMissense: likely benign (0.1941); Rare (popmax 0.252%, eas); Associated with Zellweger spectrum disorders.

What condition is associated with PEX1 p.Leu522Phe (c.1566G>C)?

PEX1 p.Leu522Phe (c.1566G>C) is associated with Zellweger spectrum disorders (ClinVar).

How common is PEX1 p.Leu522Phe (c.1566G>C) in the general population?

PEX1 p.Leu522Phe (c.1566G>C) is rare (popmax 0.252%, eas) (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.Leu522Phe (c.1566G>C)?

AlphaMissense predicts likely benign (score 0.1941) — an in-silico prediction, not a clinical call.

PEX1 p.Leu522Phe

c.1566G>C · rs145471560 · VCV1575527

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1941 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.252%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Zellweger spectrum disorders

Computational evidence

Protein change
AlphaMissense	0.1941	likely benign
REVEL	0.468	indeterminate
SaProt	LLR -7.97	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.049	GERP 1.2, phastCons 0.71
Regional constraint	o/e 0.89	unconstrained · MANE · 41 kb · p 4.3e-05 · regional, not allelic
Overall
CADD	18.08	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.252% East Asian · 112/44,456 alleles

Filtering AF 0.214% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.2%

Overall 0.00729% 113/1,550,936 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.252%	397
South Asian	0.00112%	89,240

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.Leu522Phe
Coding: c.1566G>C
MANE Select: NM_000466
dbSNP: rs145471560
Type: single nucleotide variant
Location: chr7:92510965 (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

For Zellweger syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

PEX1 c.1239+1G>T Pathogenic ★★ same condition
PEX1 c.130-1G>T Pathogenic/Likely pathogenic ★★ same condition
PEX1 c.130-2A>G Pathogenic/Likely pathogenic ★★ same condition
PEX1 c.130-2A>T Pathogenic/Likely pathogenic ★★ same condition
PEX1 c.1483+1G>A Pathogenic ★★ same condition
PEX1 c.1587+1G>A Likely pathogenic ★★ same condition
PEX1 c.1670+1G>A Pathogenic/Likely pathogenic ★★ same condition
PEX1 c.1670+1G>T 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-leu522phe (accessed [today's date]).

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