Is PEX6 p.Pro423Ala (c.1267C>G) pathogenic?

PEX6 p.Pro423Ala (c.1267C>G) is classified Uncertain significance in PEX6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-12). AlphaMissense: likely benign (0.0732); Ultra-rare (popmax 0.0169%, mid); Associated with peroxisome biogenesis disorder.

What condition is associated with PEX6 p.Pro423Ala (c.1267C>G)?

PEX6 p.Pro423Ala (c.1267C>G) is associated with peroxisome biogenesis disorder (ClinVar).

How common is PEX6 p.Pro423Ala (c.1267C>G) in the general population?

PEX6 p.Pro423Ala (c.1267C>G) is ultra-rare (popmax 0.0169%, mid) (gnomAD).

What do computational predictors say about PEX6 p.Pro423Ala (c.1267C>G)?

AlphaMissense predicts likely benign (score 0.0732) — an in-silico prediction, not a clinical call.

PEX6 p.Pro423Ala

c.1267C>G · rs774044599 · VCV1406310

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0732 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0169%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

peroxisome biogenesis disorder

Computational evidence

Protein change
AlphaMissense	0.0732	likely benign
REVEL	0.161	moderately benign-leaning
SaProt	LLR -7.06	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.07	GERP -2.8
Regional constraint	o/e 0.95	unconstrained · MANE · 10 kb · p 0.19 · regional, not allelic
Overall
CADD	6.527	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.0169% Middle Eastern · 1/5,916 alleles

Filtering AF 0.00438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.00062% 10/1,613,704 alleles · ultra-rare exomes 8/1,461,608 · genomes 2/152,096 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0169%	5,916
African / African-American	0.00935%	10,697
European (non-Finnish)	0.000169%	589,977

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: PEX6
Protein: p.Pro423Ala
Coding: c.1267C>G
MANE Select: NM_000287
dbSNP: rs774044599
Type: single nucleotide variant
Location: chr6:42969768 (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 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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.1885-1G>A Likely pathogenic ★★ same condition
PEX6 c.1962-1G>A Pathogenic/Likely pathogenic ★★ same condition
PEX6 c.2094+1G>A Likely pathogenic ★★ same condition
PEX6 c.2095-2A>G 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-pro423ala (accessed [today's date]).

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