Is PEX6 p.Val569Ala (c.1706T>C) pathogenic?

PEX6 p.Val569Ala (c.1706T>C) is classified Uncertain significance in PEX6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-21). AlphaMissense: likely benign (0.2216); Very rare (popmax 0.00578%, nfe); Associated with PEX6-related disorder.

What condition is associated with PEX6 p.Val569Ala (c.1706T>C)?

PEX6 p.Val569Ala (c.1706T>C) is associated with PEX6-related disorder, peroxisome biogenesis disorder (ClinVar).

How common is PEX6 p.Val569Ala (c.1706T>C) in the general population?

PEX6 p.Val569Ala (c.1706T>C) is very rare (popmax 0.00578%, nfe) (gnomAD).

What do computational predictors say about PEX6 p.Val569Ala (c.1706T>C)?

AlphaMissense predicts likely benign (score 0.2216) — an in-silico prediction, not a clinical call.

PEX6 p.Val569Ala

c.1706T>C · rs375243798 · VCV2194943

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2216 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00578%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PEX6-related disorder

Computational evidence

Protein change
AlphaMissense	0.2216	likely benign
REVEL	0.71	pathogenic-leaning
SaProt	LLR -9.83	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.9	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	23.1	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 0.00578% European (non-Finnish) · 68/1,175,964 alleles

Filtering AF 0.00463% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00424%

Overall 0.00424% 68/1,603,412 alleles · very rare exomes 65/1,451,326 · genomes 3/152,086 · joint denominator

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.Val569Ala
Coding: c.1706T>C
MANE Select: NM_000287
dbSNP: rs375243798
Type: single nucleotide variant
Location: chr6:42967546 (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

PEX6-related disorder

Also linked: peroxisome biogenesis disorder

Similar variants

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
PEX6 c.2095-2A>G 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-val569ala (accessed [today's date]).

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