Is PEX6 p.Arg517Pro (c.1550G>C) pathogenic?

PEX6 p.Arg517Pro (c.1550G>C) is classified Conflicting classifications of pathogenicity in PEX6 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-04-30). AlphaMissense: likely pathogenic (0.5811); Very rare (popmax 0.00168%, amr); Associated with peroxisome biogenesis disorder.

What condition is associated with PEX6 p.Arg517Pro (c.1550G>C)?

PEX6 p.Arg517Pro (c.1550G>C) is associated with peroxisome biogenesis disorder (ClinVar).

How common is PEX6 p.Arg517Pro (c.1550G>C) in the general population?

PEX6 p.Arg517Pro (c.1550G>C) is very rare (popmax 0.00168%, amr) (gnomAD).

What do computational predictors say about PEX6 p.Arg517Pro (c.1550G>C)?

AlphaMissense predicts likely pathogenic (score 0.5811) — an in-silico prediction, not a clinical call.

PEX6 p.Arg517Pro

c.1550G>C · rs371782808 · VCV501464

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.5811 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00168%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

peroxisome biogenesis disorder

Computational evidence

Protein change
AlphaMissense	0.5811	likely pathogenic
REVEL	0.842	moderately pathogenic-leaning
SaProt	LLR -13.76	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.78 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.4	GERP 0.47, phastCons 0.98
Regional constraint	o/e 0.82	unconstrained · MANE · 4,158 bp · p 6.4e-06 · regional, not allelic
Overall
CADD	25.2	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 0.00168% Admixed American · 1/59,640 alleles

Overall 0.000124% 2/1,611,738 alleles · very rare exomes 1/1,459,566 · genomes 1/152,172 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00168%	59,640
European (non-Finnish)	8.48e-05%	1,179,080

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.Arg517Pro
Coding: c.1550G>C
MANE Select: NM_000287
dbSNP: rs371782808
Type: single nucleotide variant
Location: chr6:42968428 (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 p.Arg517Gln Uncertain significance ★★ ⚠ same residue
PEX6 p.Arg517Trp Uncertain significance ★★ ⚠ same residue
PEX6 p.Arg517= Uncertain significance ★ 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-arg517pro (accessed [today's date]).

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