Is PEX1 p.Glu460Asp (c.1380A>C) pathogenic?

PEX1 p.Glu460Asp (c.1380A>C) is classified Conflicting classifications of pathogenicity in PEX1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0884); Rare (popmax 0.406%, sas); Associated with peroxisome biogenesis disorder 1A (Zellweger).

What condition is associated with PEX1 p.Glu460Asp (c.1380A>C)?

PEX1 p.Glu460Asp (c.1380A>C) is associated with peroxisome biogenesis disorder 1A (Zellweger), Zellweger spectrum disorders (ClinVar).

How common is PEX1 p.Glu460Asp (c.1380A>C) in the general population?

PEX1 p.Glu460Asp (c.1380A>C) is rare (popmax 0.406%, sas) (gnomAD).

What do computational predictors say about PEX1 p.Glu460Asp (c.1380A>C)?

AlphaMissense predicts likely benign (score 0.0884) — an in-silico prediction, not a clinical call.

PEX1 p.Glu460Asp

c.1380A>C · rs565049190 · VCV360928

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0884 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.406%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

peroxisome biogenesis disorder 1A (Zellweger)

Computational evidence

Protein change
AlphaMissense	0.0884	likely benign
REVEL	0.225	benign-leaning
SaProt	LLR -7.00	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.31	GERP 0.32, phastCons 0.3
Regional constraint	o/e 0.89	unconstrained · MANE · 41 kb · p 4.3e-05 · regional, not allelic
Overall
CADD	3.766	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 0.406% South Asian · 370/91,054 alleles

Filtering AF 0.372% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.359%

Overall 0.0239% 386/1,612,386 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.406%	246
Remaining individualsnot grpmax-eligible	0.0176%	5,679
Middle Eastern	0.0166%	6,026
East Asian	0.00223%	44,830
European (non-Finnish)	0.000254%	393,025

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.Glu460Asp
Coding: c.1380A>C
MANE Select: NM_000466
dbSNP: rs565049190
Type: single nucleotide variant
Location: chr7:92511683 (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

peroxisome biogenesis disorder 1A (Zellweger) — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Zellweger spectrum disorders

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-glu460asp (accessed [today's date]).

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