Is PEX6 p.Leu591= (c.1773C>T) pathogenic?

PEX6 p.Leu591= (c.1773C>T) is classified Likely benign in PEX6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-25). Ultra-rare (popmax 0.02%, afr); Associated with peroxisome biogenesis disorder.

What condition is associated with PEX6 p.Leu591= (c.1773C>T)?

PEX6 p.Leu591= (c.1773C>T) is associated with peroxisome biogenesis disorder (ClinVar).

How common is PEX6 p.Leu591= (c.1773C>T) in the general population?

PEX6 p.Leu591= (c.1773C>T) is ultra-rare (popmax 0.02%, afr) (gnomAD).

PEX6 p.Leu591=

c.1773C>T · rs56328719 · VCV1078973

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, afr)

Conditions

peroxisome biogenesis disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.25	GERP -1.9, phastCons 0.98
Overall
CADD	2.381	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.02% African / African-American · 15/74,884 alleles

Filtering AF 0.0123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00989%

Overall 0.00379% 61/1,610,932 alleles · ultra-rare exomes 49/1,458,794 · genomes 12/152,138 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.02%	4,992
Remaining individualsnot grpmax-eligible	0.00802%	12,474
European (non-Finnish)	0.00314%	31,864
East Asian	0.00223%	44,798
South Asian	0.00222%	45,133
Admixed American	0.00168%	59,530

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.Leu591=
Coding: c.1773C>T
MANE Select: NM_000287
dbSNP: rs56328719
Type: single nucleotide variant
Location: chr6:42967479 (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.Leu591Phe 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
PEX6 c.1962-1G>A Pathogenic/Likely pathogenic ★★ same condition
PEX6 c.2094+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-leu591 (accessed [today's date]).

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