Is PEX6 p.Pro247Arg (c.740C>G) pathogenic?

PEX6 p.Pro247Arg (c.740C>G) is classified Uncertain significance in PEX6 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-11-06). AlphaMissense: likely benign (0.1972); Ultra-rare (popmax 0.0145%, nfe); Associated with peroxisome biogenesis disorder.

What condition is associated with PEX6 p.Pro247Arg (c.740C>G)?

PEX6 p.Pro247Arg (c.740C>G) is associated with peroxisome biogenesis disorder, Zellweger spectrum disorders (ClinVar).

How common is PEX6 p.Pro247Arg (c.740C>G) in the general population?

PEX6 p.Pro247Arg (c.740C>G) is ultra-rare (popmax 0.0145%, nfe) (gnomAD).

What do computational predictors say about PEX6 p.Pro247Arg (c.740C>G)?

AlphaMissense predicts likely benign (score 0.1972) — an in-silico prediction, not a clinical call.

PEX6 p.Pro247Arg

c.740C>G · rs199697021 · VCV595555

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1972 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0145%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

peroxisome biogenesis disorder

Computational evidence

Protein change
AlphaMissense	0.1972	likely benign
REVEL	0.454	indeterminate
SaProt	LLR -7.52	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 10 kb · p 0.19 · regional, not allelic
Overall
CADD	21.9	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 0.0145% European (non-Finnish) · 171/1,180,062 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.012%

Overall 0.011% 177/1,614,098 alleles · ultra-rare exomes 161/1,461,894 · genomes 16/152,204 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0145%	6,901
Remaining individualsnot grpmax-eligible	0.0064%	15,622
Admixed American	0.00333%	29,995

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.Pro247Arg
Coding: c.740C>G
MANE Select: NM_000287
dbSNP: rs199697021
Type: single nucleotide variant
Location: chr6:42978411 (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

Also linked: Zellweger spectrum disorders

Similar variants

PEX6 p.Pro247= 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-pro247arg (accessed [today's date]).

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