Is PEX2 p.Cys138Ser (c.412T>A) pathogenic?

PEX2 p.Cys138Ser (c.412T>A) is classified Uncertain significance in PEX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-25). AlphaMissense: likely benign (0.1121); Absent from gnomAD v4.1; Associated with peroxisome biogenesis disorder 5A (Zellweger).

What condition is associated with PEX2 p.Cys138Ser (c.412T>A)?

PEX2 p.Cys138Ser (c.412T>A) is associated with peroxisome biogenesis disorder 5A (Zellweger) (ClinVar).

How common is PEX2 p.Cys138Ser (c.412T>A) in the general population?

PEX2 p.Cys138Ser (c.412T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PEX2 p.Cys138Ser (c.412T>A)?

AlphaMissense predicts likely benign (score 0.1121) — an in-silico prediction, not a clinical call.

PEX2 p.Cys138Ser

c.412T>A · rs2132044038 · VCV1430122

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1121 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

peroxisome biogenesis disorder 5A (Zellweger)

Computational evidence

Protein change
AlphaMissense	0.1121	likely benign
REVEL	0.23	benign-leaning
SaProt	LLR -5.68	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.4	GERP -0.068, phastCons 0.98
Regional constraint	o/e 0.99	unconstrained · MANE · 914 bp · p 0.85 · regional, not allelic
Overall
CADD	18.13	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PEX2
Protein: p.Cys138Ser
Coding: c.412T>A
MANE Select: NM_000318
dbSNP: rs2132044038
Type: single nucleotide variant
Location: chr8:76983767 (GRCh38)
Gene constraint: LOEUF 1.057 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.17
Residue 138: a UniProt-annotated variant site (in pbd5a); a UniProt-annotated variant site (in pbd5b and pbd5a)

Full PEX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

peroxisome biogenesis disorder 5A (Zellweger) — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PEX2 c.-17-2A>G Pathogenic/Likely pathogenic ★★ same condition
PEX2 p.Arg119Ter Pathogenic ★★ same condition
PEX2 p.Arg125Ter Pathogenic/Likely pathogenic ★★ same condition
PEX2 p.Gln31Ter Pathogenic/Likely pathogenic ★★ same condition
PEX2 p.Gln78Ter Pathogenic/Likely pathogenic ★★ same condition
PEX2 p.Gln96Ter Pathogenic ★★ same condition
PEX2 p.Glu168Ter Pathogenic/Likely pathogenic ★★ same condition
PEX2 p.Glu53Ter 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/pex2-p-cys138ser (accessed [today's date]).

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