Is PEX1 p.Arg948Trp (c.2842C>T) pathogenic?

PEX1 p.Arg948Trp (c.2842C>T) is classified Conflicting classifications of pathogenicity in PEX1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-28). AlphaMissense: likely pathogenic (0.7385); Ultra-rare (popmax 0.0383%, amr); Associated with Zellweger spectrum disorders.

What condition is associated with PEX1 p.Arg948Trp (c.2842C>T)?

PEX1 p.Arg948Trp (c.2842C>T) is associated with Zellweger spectrum disorders, peroxisome biogenesis disorder 1A (Zellweger) (ClinVar).

How common is PEX1 p.Arg948Trp (c.2842C>T) in the general population?

PEX1 p.Arg948Trp (c.2842C>T) is ultra-rare (popmax 0.0383%, amr) (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.Arg948Trp (c.2842C>T)?

AlphaMissense predicts likely pathogenic (score 0.7385) — an in-silico prediction, not a clinical call.

PEX1 p.Arg948Trp

c.2842C>T · rs374167385 · VCV282809

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.7385 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0383%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Zellweger spectrum disorders

Computational evidence

Protein change
AlphaMissense	0.7385	likely pathogenic
REVEL	0.865	moderately pathogenic-leaning
SaProt	LLR -14.40	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 9.9	GERP 3.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 41 kb · p 4.3e-05 · regional, not allelic
Overall
CADD	34.0	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 0.0383% Admixed American · 23/59,990 alleles

Filtering AF 0.0261% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0222%

Overall 0.0128% 206/1,613,770 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.382%	262
Remaining individualsnot grpmax-eligible	0.0512%	1,952
Admixed Americangrpmax	0.0383%	2,608
European (non-Finnish)	0.00305%	32,773
African / African-American	0.00267%	37,453

Ashkenazi Jewish 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.Arg948Trp
Coding: c.2842C>T
MANE Select: NM_021167 · reported on NM_000466
dbSNP: rs374167385
Type: single nucleotide variant
Location: chr7:92494571 (GRCh38)

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

Also linked: peroxisome biogenesis disorder 1A (Zellweger)

For Zellweger syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

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-arg948trp (accessed [today's date]).

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