Is PEX5 p.Gln537His (c.1611G>C) pathogenic?

PEX5 p.Gln537His (c.1611G>C) is classified Uncertain significance in PEX5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-14). AlphaMissense: likely benign (0.1287); Very rare (popmax 0.000361%, nfe); Associated with peroxisome biogenesis disorder 2B.

What condition is associated with PEX5 p.Gln537His (c.1611G>C)?

PEX5 p.Gln537His (c.1611G>C) is associated with peroxisome biogenesis disorder 2B (ClinVar).

How common is PEX5 p.Gln537His (c.1611G>C) in the general population?

PEX5 p.Gln537His (c.1611G>C) is very rare (popmax 0.000361%, nfe) (gnomAD).

What do computational predictors say about PEX5 p.Gln537His (c.1611G>C)?

AlphaMissense predicts likely benign (score 0.1287) — an in-silico prediction, not a clinical call.

PEX5 p.Gln537His

c.1611G>C · rs2540322387 · VCV1937675

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1287 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000361%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

peroxisome biogenesis disorder 2B

Computational evidence

Protein change
AlphaMissense	0.1287	likely benign
REVEL	0.338	indeterminate
SaProt	LLR -6.71	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 9.8	GERP -1.8, phastCons 1
Overall
CADD	24.2	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 0.000361% European (non-Finnish) · 4/1,108,180 alleles

Filtering AF 8.5e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.7e-05%

Overall 0.00027% 4/1,478,984 alleles · very rare exomes 4/1,404,954 · genomes 0/74,030 · 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: PEX5
Protein: p.Gln537His
Coding: c.1611G>C
MANE Select: NM_001351132
dbSNP: rs2540322387
Type: single nucleotide variant
Location: chr12:7209733 (GRCh38)
Gene constraint: LOEUF 0.768 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.28 · 11 PDB
Residue 537: a UniProt-annotated variant site (in pbd2b; impaired ability to mediate peroxisomal import of proteins containing both a c-terminal pts1- and pts2-type targeting signals)

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.Gln537Arg 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-gln537his (accessed [today's date]).

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