Is PEX1 p.Ser506Pro (c.1516T>C) pathogenic?

PEX1 p.Ser506Pro (c.1516T>C) is classified Uncertain significance in PEX1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-20). AlphaMissense: likely benign (0.0689); Very rare (popmax 0.00192%, nfe); Associated with Zellweger spectrum disorders.

What condition is associated with PEX1 p.Ser506Pro (c.1516T>C)?

PEX1 p.Ser506Pro (c.1516T>C) is associated with Zellweger spectrum disorders (ClinVar).

How common is PEX1 p.Ser506Pro (c.1516T>C) in the general population?

PEX1 p.Ser506Pro (c.1516T>C) is very rare (popmax 0.00192%, 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.Ser506Pro (c.1516T>C)?

AlphaMissense predicts likely benign (score 0.0689) — an in-silico prediction, not a clinical call.

PEX1 p.Ser506Pro

c.1516T>C · rs778220793 · VCV1444588

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0689 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00192%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Zellweger spectrum disorders

Computational evidence

Protein change
AlphaMissense	0.0689	likely benign
REVEL	0.358	indeterminate
SaProt	LLR -6.59	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.8	GERP 3.7, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 41 kb · p 4.3e-05 · regional, not allelic
Overall
CADD	14.7	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 0.00192% European (non-Finnish) · 22/1,148,186 alleles

Filtering AF 0.00125% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00107%

Overall 0.00139% 22/1,578,192 alleles · very rare exomes 21/1,425,932 · genomes 1/152,260 · joint denominator

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.Ser506Pro
Coding: c.1516T>C
MANE Select: NM_000466
dbSNP: rs778220793
Type: single nucleotide variant
Location: chr7:92511015 (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 p.Ser506= Likely benign ★ same residue
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

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-ser506pro (accessed [today's date]).

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