Is PEX6 p.Pro178Ser (c.532C>T) pathogenic?

PEX6 p.Pro178Ser (c.532C>T) is classified Uncertain significance in PEX6 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-11). AlphaMissense: likely benign (0.0787); Very rare (popmax 8.5e-05%, nfe); Associated with peroxisome biogenesis disorder.

What condition is associated with PEX6 p.Pro178Ser (c.532C>T)?

PEX6 p.Pro178Ser (c.532C>T) is associated with peroxisome biogenesis disorder (ClinVar).

How common is PEX6 p.Pro178Ser (c.532C>T) in the general population?

PEX6 p.Pro178Ser (c.532C>T) is very rare (popmax 8.5e-05%, nfe) (gnomAD).

What do computational predictors say about PEX6 p.Pro178Ser (c.532C>T)?

AlphaMissense predicts likely benign (score 0.0787) — an in-silico prediction, not a clinical call.

PEX6 p.Pro178Ser

c.532C>T · rs1331493124 · VCV843791

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0787 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.5e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

peroxisome biogenesis disorder

Computational evidence

Protein change
AlphaMissense	0.0787	likely benign
REVEL	0.233	benign-leaning
SaProt	LLR -7.07	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.1	GERP 1.5, phastCons 0.99
Regional constraint	o/e 0.95	unconstrained · MANE · 10 kb · p 0.19 · regional, not allelic
Overall
CADD	18.91	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 8.5e-05% European (non-Finnish) · 1/1,176,140 alleles

Overall 6.25e-05% 1/1,598,860 alleles · very rare exomes 1/1,446,540 · genomes 0/152,320 · 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.Pro178Ser
Coding: c.532C>T
MANE Select: NM_000287
dbSNP: rs1331493124
Type: single nucleotide variant
Location: chr6:42978619 (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

Similar variants

PEX6 p.Pro178Arg Uncertain significance ★ ⚠ same residue
PEX6 p.Pro178= 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

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-pro178ser (accessed [today's date]).

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