Is PEX1 p.Ala682Val (c.2045C>T) pathogenic?

PEX1 p.Ala682Val (c.2045C>T) is classified Conflicting classifications of pathogenicity in PEX1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0795); Ultra-rare (popmax 0.0733%, afr); Associated with Zellweger spectrum disorders.

What condition is associated with PEX1 p.Ala682Val (c.2045C>T)?

PEX1 p.Ala682Val (c.2045C>T) is associated with Zellweger spectrum disorders (ClinVar).

How common is PEX1 p.Ala682Val (c.2045C>T) in the general population?

PEX1 p.Ala682Val (c.2045C>T) is ultra-rare (popmax 0.0733%, afr) (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.Ala682Val (c.2045C>T)?

AlphaMissense predicts likely benign (score 0.0795) — an in-silico prediction, not a clinical call.

PEX1 p.Ala682Val

c.2045C>T · rs145350631 · VCV497946

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0795 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0733%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Zellweger spectrum disorders

Computational evidence

Protein change
AlphaMissense	0.0795	likely benign
REVEL	0.248	benign-leaning
SaProt	LLR -4.04	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.1	GERP 3.5, phastCons 0.81
Regional constraint	o/e 0.89	unconstrained · MANE · 41 kb · p 4.3e-05 · regional, not allelic
Overall
CADD	16.31	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 0.0733% African / African-American · 55/75,020 alleles

Filtering AF 0.0578% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0522%

Overall 0.00558% 90/1,614,082 alleles · ultra-rare exomes 57/1,461,826 · genomes 33/152,256 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0733%	1,364
Middle Eastern	0.0165%	6,058
South Asian	0.00769%	13,011
Remaining individualsnot grpmax-eligible	0.0064%	15,625
Admixed American	0.005%	20,007
European (non-Finnish)	0.00169%	59,000

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.Ala682Val
Coding: c.2045C>T
MANE Select: NM_000466
dbSNP: rs145350631
Type: single nucleotide variant
Location: chr7:92504758 (GRCh38)
Gene constraint: LOEUF 0.746 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.19
Residue 682: 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.Ala682Thr Uncertain significance ★ ⚠ same residue
PEX1 p.Ala682= Likely benign ★ 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

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-ala682val (accessed [today's date]).

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