Is PEX1 p.Val659Asp (c.1976T>A) pathogenic?

PEX1 p.Val659Asp (c.1976T>A) is classified Uncertain significance in PEX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-11). AlphaMissense: likely pathogenic (0.9759); Absent from gnomAD v4.1.

How common is PEX1 p.Val659Asp (c.1976T>A) in the general population?

PEX1 p.Val659Asp (c.1976T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PEX1 p.Val659Asp (c.1976T>A)?

AlphaMissense predicts likely pathogenic (score 0.9759) — an in-silico prediction, not a clinical call.

PEX1 p.Val659Asp

c.1976T>A · VCV3339609

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9759 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9759	likely pathogenic · top 3% in PEX1
REVEL	0.863	moderately pathogenic-leaning
SaProt	LLR -18.58	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 4.3, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 41 kb · p 4.3e-05 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PEX1
Protein: p.Val659Asp
Coding: c.1976T>A
MANE Select: NM_000466
Type: single nucleotide variant
Location: chr7:92504827 (GRCh38)
Gene constraint: LOEUF 0.746 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.19
Residue 659: a UniProt-annotated variant site (in pbd1a and pbd1b)

Full PEX1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PEX1 p.Val659Phe Uncertain significance ★★ ⚠ same residue
PEX1 p.Val659= Likely benign ★★ same residue
PEX1 p.Val659Gly Likely pathogenic ★ same residue
PEX1 p.Val659Ile Likely benign ★ same residue
PEX1 c.1239+1G>T Pathogenic ★★ same type
PEX1 c.130-1G>T Pathogenic/Likely pathogenic ★★ same type
PEX1 c.130-2A>G Pathogenic/Likely pathogenic ★★ same type
PEX1 c.130-2A>T Pathogenic/Likely pathogenic ★★ same type

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-val659asp (accessed [today's date]).

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