Is PEX6 p.Arg888Pro (c.2663G>C) pathogenic?

PEX6 p.Arg888Pro (c.2663G>C) is classified Conflicting classifications of pathogenicity in PEX6 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-03-29). AlphaMissense: likely pathogenic (0.8401); Absent from gnomAD v4.1; Associated with peroxisome biogenesis disorder 4A (Zellweger).

What condition is associated with PEX6 p.Arg888Pro (c.2663G>C)?

PEX6 p.Arg888Pro (c.2663G>C) is associated with peroxisome biogenesis disorder 4A (Zellweger), peroxisome biogenesis disorder 4B (ClinVar).

How common is PEX6 p.Arg888Pro (c.2663G>C) in the general population?

PEX6 p.Arg888Pro (c.2663G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PEX6 p.Arg888Pro (c.2663G>C)?

AlphaMissense predicts likely pathogenic (score 0.8401) — an in-silico prediction, not a clinical call.

PEX6 p.Arg888Pro

c.2663G>C · rs267608247 · VCV931051

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8401 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

peroxisome biogenesis disorder 4A (Zellweger)

Computational evidence

Protein change
AlphaMissense	0.8401	likely pathogenic
REVEL	0.947	strongly pathogenic-leaning
SaProt	LLR -16.68	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.25	donor loss, 3 bp away · masked 0 · deltas
Pangolin	Δ0.28	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5.9	GERP 0.46, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 4,158 bp · p 6.4e-06 · regional, not allelic
Overall
CADD	27.9	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

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: PEX6
Protein: p.Arg888Pro
Coding: c.2663G>C
MANE Select: NM_000287
dbSNP: rs267608247
Type: single nucleotide variant
Location: chr6:42965078 (GRCh38)
Gene constraint: LOEUF 0.799 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.87

Full PEX6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

peroxisome biogenesis disorder 4A (Zellweger) — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: peroxisome biogenesis disorder 4B

Similar variants

PEX6 p.Arg888His Conflicting classifications of pathogenicity ★ ⚠ same residue
PEX6 p.Arg888Cys Uncertain significance ★ ⚠ same residue
PEX6 p.Arg888Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
PEX6 c.1130+1G>A Likely pathogenic ★★ same condition
PEX6 c.1233+1G>A Likely pathogenic ★★ same condition
PEX6 c.1688+1G>A Pathogenic ★★ same condition
PEX6 c.1689-1G>A Likely pathogenic ★★ same condition
PEX6 c.1961+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/pex6-p-arg888pro (accessed [today's date]).

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