Is PEX6 p.Ala186Val (c.557C>T) pathogenic?

PEX6 p.Ala186Val (c.557C>T) is classified Uncertain significance in PEX6 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-04-06). AlphaMissense: likely benign (0.1918); Very rare (popmax 0.000339%, nfe); Associated with Zellweger spectrum disorders.

What condition is associated with PEX6 p.Ala186Val (c.557C>T)?

PEX6 p.Ala186Val (c.557C>T) is associated with Zellweger spectrum disorders (ClinVar).

How common is PEX6 p.Ala186Val (c.557C>T) in the general population?

PEX6 p.Ala186Val (c.557C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

How is Zellweger syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PEX6 p.Ala186Val (c.557C>T)?

AlphaMissense predicts likely benign (score 0.1918) — an in-silico prediction, not a clinical call.

PEX6 p.Ala186Val

c.557C>T · VCV4059644

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1918 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Zellweger spectrum disorders

Computational evidence

Protein change
AlphaMissense	0.1918	likely benign
REVEL	0.486	indeterminate
SaProt	LLR -6.75	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 10 kb · p 0.19 · regional, not allelic
Overall
CADD	26.6	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 0.000339% European (non-Finnish) · 4/1,179,556 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000311% 5/1,610,028 alleles · very rare exomes 4/1,457,868 · genomes 1/152,160 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00164%	60,906
European (non-Finnish)grpmax	0.000339%	294,889

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala186Val
Coding: c.557C>T
MANE Select: NM_000287
Type: single nucleotide variant
Location: chr6:42978594 (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

Zellweger spectrum disorders — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Zellweger syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

PEX6 p.Ala186= Likely benign ★ same residue
PEX6 c.1130+1G>A Likely pathogenic ★★ same condition
PEX6 c.1233+1G>A Likely pathogenic ★★ same condition
PEX6 c.1962-1G>A Pathogenic/Likely pathogenic ★★ same condition
PEX6 c.2362+1G>A Likely pathogenic ★★ same condition
PEX6 c.2589-1G>T Likely pathogenic ★★ same condition
PEX6 c.2807-2A>G Pathogenic/Likely pathogenic ★★ same condition
PEX6 c.882+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-ala186val (accessed [today's date]).

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