Is PEX6 p.Arg786Trp (c.2356C>T) pathogenic?

PEX6 p.Arg786Trp (c.2356C>T) is classified Conflicting classifications of pathogenicity in PEX6 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-11-18). AlphaMissense: likely pathogenic (0.87); Very rare (popmax 0.00119%, nfe); Associated with PEX6-related disorder.

What condition is associated with PEX6 p.Arg786Trp (c.2356C>T)?

PEX6 p.Arg786Trp (c.2356C>T) is associated with PEX6-related disorder, cerebellar ataxia, premature menopause (ClinVar).

How common is PEX6 p.Arg786Trp (c.2356C>T) in the general population?

PEX6 p.Arg786Trp (c.2356C>T) is very rare (popmax 0.00119%, nfe) (gnomAD).

What do computational predictors say about PEX6 p.Arg786Trp (c.2356C>T)?

AlphaMissense predicts likely pathogenic (score 0.87) — an in-silico prediction, not a clinical call.

PEX6 p.Arg786Trp

c.2356C>T · rs267608239 · VCV553552

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.87 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PEX6-related disorder

Computational evidence

Protein change
AlphaMissense	0.87	likely pathogenic · top 10% in PEX6
REVEL	0.934	strongly pathogenic-leaning
SaProt	LLR -13.13	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Pangolin	Δ0.29	loss · gain 0.01 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 6.3	GERP 0.44, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 4,158 bp · p 6.4e-06 · regional, not allelic
Overall
CADD	33.0	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 0.00119% European (non-Finnish) · 14/1,179,998 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000867% 14/1,613,890 alleles · very rare exomes 13/1,461,734 · genomes 1/152,156 · 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.Arg786Trp
Coding: c.2356C>T
MANE Select: NM_000287
dbSNP: rs267608239
Type: single nucleotide variant
Location: chr6:42966050 (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: cerebellar ataxia premature menopause peripheral neuropathy peroxisome biogenesis disorder 4A (Zellweger)peroxisome biogenesis disorder 4B paroxysmal dystonia peroxisome biogenesis disorder sensorineural hearing loss disorder

Similar variants

PEX6 p.Arg786Gln 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.1961+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-arg786trp (accessed [today's date]).

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