Is PEX2 p.Ala304Val (c.911C>T) pathogenic?

PEX2 p.Ala304Val (c.911C>T) is classified Uncertain significance in PEX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-28). AlphaMissense: likely benign (0.0804); Very rare (popmax 0.00666%, afr); Associated with peroxisome biogenesis disorder 5A (Zellweger).

What condition is associated with PEX2 p.Ala304Val (c.911C>T)?

PEX2 p.Ala304Val (c.911C>T) is associated with peroxisome biogenesis disorder 5A (Zellweger) (ClinVar).

How common is PEX2 p.Ala304Val (c.911C>T) in the general population?

PEX2 p.Ala304Val (c.911C>T) is very rare (popmax 0.00666%, afr) (gnomAD).

What do computational predictors say about PEX2 p.Ala304Val (c.911C>T)?

AlphaMissense predicts likely benign (score 0.0804) — an in-silico prediction, not a clinical call.

PEX2 p.Ala304Val

c.911C>T · rs558586088 · VCV2084006

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0804 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00666%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

peroxisome biogenesis disorder 5A (Zellweger)

Computational evidence

Protein change
AlphaMissense	0.0804	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -5.56	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP 0.73, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 914 bp · p 0.85 · regional, not allelic
Overall
CADD	18.29	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 0.00666% African / African-American · 5/75,044 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.000434% 7/1,612,508 alleles · very rare exomes 5/1,460,222 · genomes 2/152,286 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00666%	15,009
East Asian	0.00223%	44,872
European (non-Finnish)	8.47e-05%	1,179,954

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.Ala304Val
Coding: c.911C>T
MANE Select: NM_000318
dbSNP: rs558586088
Type: single nucleotide variant
Location: chr8:76983268 (GRCh38)
Gene constraint: LOEUF 1.057 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.17
Residue 304: a UniProt-annotated variant site (in pbd5a); a UniProt-annotated variant site (in pbd5b and pbd5a); a UniProt-annotated variant site (in pbd5b)

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 p.Ala304= 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
PEX2 p.Glu168Ter 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-ala304val (accessed [today's date]).

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