Is PEX1 p.Asn423Ser (c.1268A>G) pathogenic?

PEX1 p.Asn423Ser (c.1268A>G) is classified Benign in PEX1 (ClinVar, Single submitter, 3 submitters; last evaluated 2025-11-17). AlphaMissense: likely benign (0.1034); Very rare (popmax 0.000607%, nfe); Associated with Zellweger spectrum disorders.

What condition is associated with PEX1 p.Asn423Ser (c.1268A>G)?

PEX1 p.Asn423Ser (c.1268A>G) is associated with Zellweger spectrum disorders (ClinVar).

How common is PEX1 p.Asn423Ser (c.1268A>G) in the general population?

PEX1 p.Asn423Ser (c.1268A>G) is very rare (popmax 0.000607%, 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.Asn423Ser (c.1268A>G)?

AlphaMissense predicts likely benign (score 0.1034) — an in-silico prediction, not a clinical call.

PEX1 p.Asn423Ser

c.1268A>G · rs200857848 · VCV766340

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1034 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000607%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Zellweger spectrum disorders

Computational evidence

Protein change
AlphaMissense	0.1034	likely benign
REVEL	0.417	indeterminate
SaProt	LLR -3.82	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 4.2	GERP 4.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 41 kb · p 4.3e-05 · regional, not allelic
Overall
CADD	19.72	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 0.000607% European (non-Finnish) · 7/1,153,732 alleles

Filtering AF 0.000252% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000162%

Overall 0.00834% 132/1,583,570 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.196%	510
Remaining individualsnot grpmax-eligible	0.00163%	61,438
European (non-Finnish)grpmax	0.000607%	164,819

Finnish 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.Asn423Ser
Coding: c.1268A>G
MANE Select: NM_000466
dbSNP: rs200857848
Type: single nucleotide variant
Location: chr7:92513939 (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-asn423ser (accessed [today's date]).

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