Is PEX6 p.Pro697Ser (c.2089C>T) pathogenic?

PEX6 p.Pro697Ser (c.2089C>T) is classified Uncertain significance in PEX6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-05-20). AlphaMissense: ambiguous (0.4998); Ultra-rare (popmax 0.02%, afr); Associated with Heimler syndrome 2.

What condition is associated with PEX6 p.Pro697Ser (c.2089C>T)?

PEX6 p.Pro697Ser (c.2089C>T) is associated with Heimler syndrome 2, peroxisome biogenesis disorder (ClinVar).

How common is PEX6 p.Pro697Ser (c.2089C>T) in the general population?

PEX6 p.Pro697Ser (c.2089C>T) is ultra-rare (popmax 0.02%, afr) (gnomAD).

What do computational predictors say about PEX6 p.Pro697Ser (c.2089C>T)?

AlphaMissense predicts ambiguous (score 0.4998) — an in-silico prediction, not a clinical call.

PEX6 p.Pro697Ser

c.2089C>T · rs543110086 · VCV1031507

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4998 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Heimler syndrome 2

Computational evidence

Protein change
AlphaMissense	0.4998	ambiguous
REVEL	0.789	moderately pathogenic-leaning
SaProt	LLR -11.62	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	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	27.0	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 0.02% African / African-American · 15/75,034 alleles

Filtering AF 0.0123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00988%

Overall 0.000929% 15/1,614,148 alleles · ultra-rare exomes 11/1,461,890 · genomes 4/152,258 · 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.Pro697Ser
Coding: c.2089C>T
MANE Select: NM_000287
dbSNP: rs543110086
Type: single nucleotide variant
Location: chr6:42966530 (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

Heimler syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: peroxisome biogenesis disorder

Similar variants

PEX6 p.Pro697= Likely benign ★ 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-pro697ser (accessed [today's date]).

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