Is PEX5 p.Arg394Ser (c.1182G>T) pathogenic?

PEX5 p.Arg394Ser (c.1182G>T) is classified Uncertain significance in PEX5 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-03-11). AlphaMissense: ambiguous (0.4972); Ultra-rare (popmax 0.0176%, sas); Associated with peroxisome biogenesis disorder 2B.

What condition is associated with PEX5 p.Arg394Ser (c.1182G>T)?

PEX5 p.Arg394Ser (c.1182G>T) is associated with peroxisome biogenesis disorder 2B (ClinVar).

How common is PEX5 p.Arg394Ser (c.1182G>T) in the general population?

PEX5 p.Arg394Ser (c.1182G>T) is ultra-rare (popmax 0.0176%, sas) (gnomAD).

What do computational predictors say about PEX5 p.Arg394Ser (c.1182G>T)?

AlphaMissense predicts ambiguous (score 0.4972) — an in-silico prediction, not a clinical call.

PEX5 p.Arg394Ser

c.1182G>T · rs199624284 · VCV1379917

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4972 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0176%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

peroxisome biogenesis disorder 2B

Computational evidence

Protein change
AlphaMissense	0.4972	ambiguous
REVEL	0.268	benign-leaning
SaProt	LLR -10.59	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	Δ0.34	acceptor gain · deltas
Pangolin	Δ0.46	loss · gain 0.37 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP 4.8	GERP -0.26, phastCons 1
Overall
CADD	34.0	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 0.0176% South Asian · 16/91,018 alleles

Filtering AF 0.011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00899%

Overall 0.00105% 17/1,611,618 alleles · ultra-rare exomes 15/1,459,422 · genomes 2/152,196 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0176%	5,689
European (non-Finnish)	8.49e-05%	1,177,858

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: PEX5
Protein: p.Arg394Ser
Coding: c.1182G>T
MANE Select: NM_001351132
dbSNP: rs199624284
Type: single nucleotide variant
Location: chr12:7208457 (GRCh38)
Gene constraint: LOEUF 0.768 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.28 · 11 PDB
Residue 394: an α-helix

Full PEX5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

peroxisome biogenesis disorder 2B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PEX5 p.Arg394= Uncertain significance ★ same residue
PEX5 c.449-2A>G Pathogenic/Likely pathogenic ★★ same condition
PEX5 c.552-1G>A Pathogenic/Likely pathogenic ★★ same condition
PEX5 c.847-2A>G Likely pathogenic ★★ same condition
PEX5 c.967-1G>A Likely pathogenic ★★ same condition
PEX5 p.Arg237Ter Pathogenic/Likely pathogenic ★★ same condition
PEX5 p.Arg276Ter Pathogenic/Likely pathogenic ★★ same condition
PEX5 p.Arg420Ter 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/pex5-p-arg394ser (accessed [today's date]).

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