Is PEX3 p.Gly331Arg (c.991G>A) pathogenic?

PEX3 p.Gly331Arg (c.991G>A) is classified Conflicting classifications of pathogenicity in PEX3 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-08-16). AlphaMissense: likely pathogenic (0.9265); Very rare (popmax 0.000596%, nfe); Associated with PEX3-related disorder.

What condition is associated with PEX3 p.Gly331Arg (c.991G>A)?

PEX3 p.Gly331Arg (c.991G>A) is associated with PEX3-related disorder, peroxisome biogenesis disorder 10B (ClinVar).

How common is PEX3 p.Gly331Arg (c.991G>A) in the general population?

PEX3 p.Gly331Arg (c.991G>A) is very rare (popmax 0.000596%, nfe) (gnomAD).

What do computational predictors say about PEX3 p.Gly331Arg (c.991G>A)?

AlphaMissense predicts likely pathogenic (score 0.9265) — an in-silico prediction, not a clinical call.

PEX3 p.Gly331Arg

c.991G>A · rs1057523689 · VCV390240

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9265 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000596%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

PEX3-related disorder

Computational evidence

Protein change
AlphaMissense	0.9265	likely pathogenic
REVEL	0.324	indeterminate
SaProt	LLR -3.24	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.36	donor loss · deltas
Pangolin	Δ0.54	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.3, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 38 kb · p 8.4e-05 · regional, not allelic
Overall
CADD	29.6	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 0.000596% European (non-Finnish) · 7/1,174,234 alleles

Filtering AF 0.000248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000435% 7/1,607,402 alleles · very rare exomes 7/1,455,296 · genomes 0/152,106 · 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: PEX3
Protein: p.Gly331Arg
Coding: c.991G>A
MANE Select: NM_003630
dbSNP: rs1057523689
Type: single nucleotide variant
Location: chr6:143485201 (GRCh38)
Gene constraint: LOEUF 0.972 · pLI 0.12 (gnomAD)
Structure: AlphaFold pLDDT 88.94 · 2 PDB
Residue 331: a UniProt-annotated variant site (in pbd10b)

Full PEX3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

PEX3-related disorder

Also linked: peroxisome biogenesis disorder 10B

Similar variants

PEX3 p.Gly331= Likely benign ★ same residue
PEX3 c.942-1G>T Likely pathogenic ★★ same condition
PEX3 p.Arg256Ter Pathogenic/Likely pathogenic ★★ same condition
PEX3 p.Glu266Asp Uncertain significance ★★ ⚠ same condition
PEX3 c.524-19T>C Benign ★★ same condition
PEX3 c.579-1G>A Likely pathogenic ★ same condition
PEX3 p.Trp6Arg Uncertain significance ★ ⚠ same condition
PEX3 p.Arg300Ter 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/pex3-p-gly331arg (accessed [today's date]).

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