Is PEX6 p.Pro728Ser (c.2182C>T) pathogenic?

PEX6 p.Pro728Ser (c.2182C>T) is classified Conflicting classifications of pathogenicity in PEX6 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-13). AlphaMissense: likely benign (0.3125); Rare (popmax 0.162%, sas); Associated with peroxisome biogenesis disorder.

What condition is associated with PEX6 p.Pro728Ser (c.2182C>T)?

PEX6 p.Pro728Ser (c.2182C>T) is associated with peroxisome biogenesis disorder (ClinVar).

How common is PEX6 p.Pro728Ser (c.2182C>T) in the general population?

PEX6 p.Pro728Ser (c.2182C>T) is rare (popmax 0.162%, sas) (gnomAD).

What do computational predictors say about PEX6 p.Pro728Ser (c.2182C>T)?

AlphaMissense predicts likely benign (score 0.3125) — an in-silico prediction, not a clinical call.

PEX6 p.Pro728Ser

c.2182C>T · rs577794661 · VCV595375

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3125 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.162%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

peroxisome biogenesis disorder

Computational evidence

Protein change
AlphaMissense	0.3125	likely benign
REVEL	0.86	moderately pathogenic-leaning
SaProt	LLR -9.60	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 9.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 4,158 bp · p 6.4e-06 · regional, not allelic
Overall
CADD	27.6	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 0.162% South Asian · 148/91,084 alleles

Filtering AF 0.141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.133%

Overall 0.00948% 153/1,613,984 alleles · rare exomes 143/1,461,698 · genomes 10/152,286 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.162%	615
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0032%	31,254
African / African-American	0.00133%	75,034
European (non-Finnish)	8.47e-05%	1,179,990

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.Pro728Ser
Coding: c.2182C>T
MANE Select: NM_000287
dbSNP: rs577794661
Type: single nucleotide variant
Location: chr6:42966360 (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.Pro728Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
PEX6 p.Pro728= 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-pro728ser (accessed [today's date]).

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