Is PEX5 p.Met613Val (c.1837A>G) pathogenic?

PEX5 p.Met613Val (c.1837A>G) is classified Uncertain significance in PEX5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-08). AlphaMissense: likely benign (0.3203); Very rare (popmax 0.00458%, nfe); Associated with peroxisome biogenesis disorder 2B.

What condition is associated with PEX5 p.Met613Val (c.1837A>G)?

PEX5 p.Met613Val (c.1837A>G) is associated with peroxisome biogenesis disorder 2B (ClinVar).

How common is PEX5 p.Met613Val (c.1837A>G) in the general population?

PEX5 p.Met613Val (c.1837A>G) is very rare (popmax 0.00458%, nfe) (gnomAD).

What do computational predictors say about PEX5 p.Met613Val (c.1837A>G)?

AlphaMissense predicts likely benign (score 0.3203) — an in-silico prediction, not a clinical call.

PEX5 p.Met613Val

c.1837A>G · rs765623850 · VCV858721

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3203 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00458%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

peroxisome biogenesis disorder 2B

Computational evidence

Protein change
AlphaMissense	0.3203	likely benign
REVEL	0.511	indeterminate
SaProt	LLR -11.67	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.66, phastCons 1
Overall
CADD	23.2	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 0.00458% European (non-Finnish) · 54/1,180,030 alleles

Filtering AF 0.00358% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00321%

Overall 0.00471% 76/1,614,068 alleles · very rare exomes 73/1,461,884 · genomes 3/152,184 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.025%	4,002
European (non-Finnish)grpmax	0.00458%	21,852
South Asian	0.00439%	22,773
Remaining individualsnot grpmax-eligible	0.0016%	62,486
African / African-American	0.00133%	74,916

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Met613Val
Coding: c.1837A>G
MANE Select: NM_001351132
dbSNP: rs765623850
Type: single nucleotide variant
Location: chr12:7210140 (GRCh38)
Gene constraint: LOEUF 0.768 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.28 · 11 PDB
Residue 613: 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); 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.Met613Ile Uncertain significance ★ ⚠ same residue
PEX5 p.Met613Thr 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

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-met613val (accessed [today's date]).

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