Is PEX1 p.Arg581Pro (c.1742G>C) pathogenic?

PEX1 p.Arg581Pro (c.1742G>C) is classified Pathogenic/Likely pathogenic in PEX1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-03-18). AlphaMissense: likely pathogenic (0.8337); Very rare (popmax 0.00119%, nfe); Associated with PEX1-related disorder.

What condition is associated with PEX1 p.Arg581Pro (c.1742G>C)?

PEX1 p.Arg581Pro (c.1742G>C) is associated with PEX1-related disorder, peroxisome biogenesis disorder 1A (Zellweger), peroxisome biogenesis disorder 1B (ClinVar).

How common is PEX1 p.Arg581Pro (c.1742G>C) in the general population?

PEX1 p.Arg581Pro (c.1742G>C) is very rare (popmax 0.00119%, nfe) (gnomAD).

What do computational predictors say about PEX1 p.Arg581Pro (c.1742G>C)?

AlphaMissense predicts likely pathogenic (score 0.8337) — an in-silico prediction, not a clinical call.

PEX1 p.Arg581Pro

c.1742G>C · rs370483961 · VCV217429

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.8337 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PEX1-related disorder

Computational evidence

Protein change
AlphaMissense	0.8337	likely pathogenic ✓ concordant with ClinVar
REVEL	0.729	pathogenic-leaning
SaProt	LLR -12.67	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 4.4, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 41 kb · p 4.3e-05 · regional, not allelic
Overall
CADD	26.0	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 0.00119% European (non-Finnish) · 14/1,179,932 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00103% 15/1,461,814 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,502
European (non-Finnish)grpmax	0.00119%	84,281

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg581Pro
Coding: c.1742G>C
MANE Select: NM_000466
dbSNP: rs370483961
Type: single nucleotide variant
Location: chr7:92507055 (GRCh38)
Gene constraint: LOEUF 0.746 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.19
Residue 581: a UniProt-annotated variant site (in hmlr1; results in mild functional decrease in peroxisome biogenesis)

Full PEX1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

PEX1-related disorder

Also linked: peroxisome biogenesis disorder 1A (Zellweger)peroxisome biogenesis disorder 1B Zellweger spectrum disorders

Similar variants

PEX1 p.Arg581Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
PEX1 p.Arg581Trp Uncertain significance ★ ⚠ same residue
PEX1 p.Arg581_Ser585del Pathogenic ★ 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

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-arg581pro (accessed [today's date]).

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