Is PEX1 p.Arg949Gln (c.2846G>A) pathogenic?

PEX1 p.Arg949Gln (c.2846G>A) is classified Pathogenic/Likely pathogenic in PEX1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-10). AlphaMissense: likely pathogenic (0.9251); Very rare (popmax 0.00356%, nfe); Associated with Zellweger spectrum disorders.

What condition is associated with PEX1 p.Arg949Gln (c.2846G>A)?

PEX1 p.Arg949Gln (c.2846G>A) is associated with Zellweger spectrum disorders, peroxisome biogenesis disorder 1A (Zellweger) (ClinVar).

How common is PEX1 p.Arg949Gln (c.2846G>A) in the general population?

PEX1 p.Arg949Gln (c.2846G>A) is very rare (popmax 0.00356%, 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.Arg949Gln (c.2846G>A)?

AlphaMissense predicts likely pathogenic (score 0.9251) — an in-silico prediction, not a clinical call.

PEX1 p.Arg949Gln

c.2846G>A · rs61750425 · VCV556176

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9251 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00356%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Zellweger spectrum disorders

Computational evidence

Protein change
AlphaMissense	0.9251	likely pathogenic ✓ concordant with ClinVar
REVEL	0.941	strongly pathogenic-leaning
SaProt	LLR -12.31	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.7	GERP 3.9, phastCons 0.97
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 0.00356% European (non-Finnish) · 42/1,179,794 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.00285% 46/1,613,738 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00356%	28,090
African / African-American	0.00267%	37,453
Admixed American	0.00167%	59,986
South Asian	0.0011%	91,086

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.Arg949Gln
Coding: c.2846G>A
MANE Select: NM_021167 · reported on NM_000466
dbSNP: rs61750425
Type: single nucleotide variant
Location: chr7:92494567 (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-arg949gln (accessed [today's date]).

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