Is PEX1 p.Asp665= (c.1995C>T) pathogenic?

PEX1 p.Asp665= (c.1995C>T) is classified Likely benign in PEX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-30). Very rare (popmax 0.00339%, nfe); Associated with Zellweger spectrum disorders.

What condition is associated with PEX1 p.Asp665= (c.1995C>T)?

PEX1 p.Asp665= (c.1995C>T) is associated with Zellweger spectrum disorders (ClinVar).

How common is PEX1 p.Asp665= (c.1995C>T) in the general population?

PEX1 p.Asp665= (c.1995C>T) is very rare (popmax 0.00339%, nfe) (gnomAD).

How is Zellweger syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

PEX1 p.Asp665=

c.1995C>T · rs758706584 · VCV758476

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00339%, nfe)

Conditions

Zellweger spectrum disorders

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.23	GERP -5.7, phastCons 0.59
Overall
CADD	2.831	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00339% European (non-Finnish) · 40/1,179,940 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00225%

Overall 0.0026% 42/1,613,942 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00339%	29,499
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.Asp665=
Coding: c.1995C>T
MANE Select: NM_000466
dbSNP: rs758706584
Type: single nucleotide variant
Location: chr7:92504808 (GRCh38)
Gene constraint: LOEUF 0.746 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.19
Residue 665: a UniProt-annotated variant site (in pbd1a and pbd1b)

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 p.Asp665Ala Uncertain significance ★ ⚠ 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
PEX1 c.1587+1G>A Likely pathogenic ★★ same condition
PEX1 c.1670+1G>A Pathogenic/Likely 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-asp665 (accessed [today's date]).

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