Is PEX6 p.Arg522Pro (c.1565G>C) pathogenic?

PEX6 p.Arg522Pro (c.1565G>C) is classified Uncertain significance in PEX6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-28). AlphaMissense: ambiguous (0.4521); Very rare (popmax 0.00254%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PEX6 p.Arg522Pro (c.1565G>C)?

PEX6 p.Arg522Pro (c.1565G>C) is associated with Inborn genetic diseases, peroxisome biogenesis disorder (ClinVar).

How common is PEX6 p.Arg522Pro (c.1565G>C) in the general population?

PEX6 p.Arg522Pro (c.1565G>C) is very rare (popmax 0.00254%, nfe) (gnomAD).

What do computational predictors say about PEX6 p.Arg522Pro (c.1565G>C)?

AlphaMissense predicts ambiguous (score 0.4521) — an in-silico prediction, not a clinical call.

PEX6 p.Arg522Pro

c.1565G>C · rs374396138 · VCV2142461

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4521 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00254%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4521	ambiguous
REVEL	0.463	indeterminate
SaProt	LLR -9.22	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 4,158 bp · p 6.4e-06 · regional, not allelic
Overall
CADD	27.7	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 0.00254% European (non-Finnish) · 30/1,179,878 alleles

Filtering AF 0.0018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00156%

Overall 0.00192% 31/1,613,584 alleles · very rare exomes 22/1,461,380 · genomes 9/152,204 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00254%	39,329
Remaining individualsnot grpmax-eligible	0.0016%	62,448

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.Arg522Pro
Coding: c.1565G>C
MANE Select: NM_000287
dbSNP: rs374396138
Type: single nucleotide variant
Location: chr6:42968413 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: peroxisome biogenesis disorder

Similar variants

PEX6 p.Arg522Trp Uncertain significance ★★ ⚠ same residue
PEX6 p.Arg522Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
PEX6 p.Arg522= Likely benign ★ 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.1885-1G>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-arg522pro (accessed [today's date]).

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