Is PEX2 p.Phe41Leu (c.123T>A) pathogenic?

PEX2 p.Phe41Leu (c.123T>A) is classified Uncertain significance in PEX2 (ClinVar, Single submitter, 2 submitters; last evaluated 2021-12-02). AlphaMissense: likely pathogenic (0.8024); Very rare (popmax 6.2e-05%); Associated with peroxisome biogenesis disorder 5A (Zellweger).

What condition is associated with PEX2 p.Phe41Leu (c.123T>A)?

PEX2 p.Phe41Leu (c.123T>A) is associated with peroxisome biogenesis disorder 5A (Zellweger), Zellweger spectrum disorders (ClinVar).

How common is PEX2 p.Phe41Leu (c.123T>A) in the general population?

PEX2 p.Phe41Leu (c.123T>A) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about PEX2 p.Phe41Leu (c.123T>A)?

AlphaMissense predicts likely pathogenic (score 0.8024) — an in-silico prediction, not a clinical call.

PEX2 p.Phe41Leu

c.123T>A · rs2132044807 · VCV1505989

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8024 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

peroxisome biogenesis disorder 5A (Zellweger)

Computational evidence

Protein change
AlphaMissense	0.8024	likely pathogenic · top 8% in PEX2
REVEL	0.499	indeterminate
SaProt	LLR -4.86	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.9	GERP -4.9, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 914 bp · p 0.85 · regional, not allelic
Overall
CADD	21.8	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 6.2e-05%

Overall 6.2e-05% 1/1,612,920 alleles · very rare exomes 1/1,460,616 · genomes 0/152,304 · 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: PEX2
Protein: p.Phe41Leu
Coding: c.123T>A
MANE Select: NM_000318
dbSNP: rs2132044807
Type: single nucleotide variant
Location: chr8:76984056 (GRCh38)
Gene constraint: LOEUF 1.057 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.17
Residue 41: a UniProt-annotated variant site (in 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

Also linked: Zellweger spectrum disorders

Similar variants

PEX2 p.Phe41Tyr Uncertain significance ★ ⚠ same residue
PEX2 p.Phe41= Likely benign ★ same residue
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

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-phe41leu (accessed [today's date]).

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