Is PEX6 p.Leu499Phe (c.1495C>T) pathogenic?

PEX6 p.Leu499Phe (c.1495C>T) is classified Uncertain significance in PEX6 (ClinVar, Single submitter, 2 submitters; last evaluated 2021-08-30). AlphaMissense: likely benign (0.1661); Very rare (popmax 0.00573%, sas); Associated with peroxisome biogenesis disorder.

What condition is associated with PEX6 p.Leu499Phe (c.1495C>T)?

PEX6 p.Leu499Phe (c.1495C>T) is associated with peroxisome biogenesis disorder, Zellweger spectrum disorders (ClinVar).

How common is PEX6 p.Leu499Phe (c.1495C>T) in the general population?

PEX6 p.Leu499Phe (c.1495C>T) is very rare (popmax 0.00573%, sas) (gnomAD).

What do computational predictors say about PEX6 p.Leu499Phe (c.1495C>T)?

AlphaMissense predicts likely benign (score 0.1661) — an in-silico prediction, not a clinical call.

PEX6 p.Leu499Phe

c.1495C>T · rs769207892 · VCV1013894

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1661 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00573%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

peroxisome biogenesis disorder

Computational evidence

Protein change
AlphaMissense	0.1661	likely benign
REVEL	0.549	indeterminate
SaProt	LLR -12.68	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.9	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	26.1	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 0.00573% South Asian · 5/87,274 alleles

Filtering AF 0.00217% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.000507% 8/1,578,526 alleles · very rare exomes 8/1,426,158 · genomes 0/152,368 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00573%	17,455
East Asian	0.00467%	21,407
Remaining individualsnot grpmax-eligible	0.00164%	61,146

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.Leu499Phe
Coding: c.1495C>T
MANE Select: NM_000287
dbSNP: rs769207892
Type: single nucleotide variant
Location: chr6:42968483 (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

Also linked: Zellweger spectrum disorders

Similar variants

PEX6 p.Leu499= Likely benign ★ same residue
PEX6 p.Leu499fs Pathogenic ★ 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

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-leu499phe (accessed [today's date]).

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