Is PEX2 p.Ala74= (c.222C>T) pathogenic?

PEX2 p.Ala74= (c.222C>T) is classified Likely benign in PEX2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-18). Ultra-rare (popmax 0.0147%, afr); Associated with peroxisome biogenesis disorder 5A (Zellweger).

What condition is associated with PEX2 p.Ala74= (c.222C>T)?

PEX2 p.Ala74= (c.222C>T) is associated with peroxisome biogenesis disorder 5A (Zellweger) (ClinVar).

How common is PEX2 p.Ala74= (c.222C>T) in the general population?

PEX2 p.Ala74= (c.222C>T) is ultra-rare (popmax 0.0147%, afr) (gnomAD).

PEX2 p.Ala74=

c.222C>T · rs370886270 · VCV1666824

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, afr)

Conditions

peroxisome biogenesis disorder 5A (Zellweger)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 0.75, phastCons 1
Overall
CADD	8.404	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0147% African / African-American · 11/74,896 alleles

Filtering AF 0.00816% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.000991% 16/1,614,002 alleles · ultra-rare exomes 8/1,461,860 · genomes 8/152,142 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0147%	6,809
Admixed American	0.00333%	29,999
South Asian	0.0022%	45,545
European (non-Finnish)	8.47e-05%	1,180,016

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.Ala74=
Coding: c.222C>T
MANE Select: NM_000318
dbSNP: rs370886270
Type: single nucleotide variant
Location: chr8:76983957 (GRCh38)
Gene constraint: LOEUF 1.057 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.17
Residue 74: 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

Similar variants

PEX2 p.Ala74Gly Uncertain significance ★ ⚠ same residue
PEX2 p.Ala74Val Uncertain significance ★ ⚠ same residue
PEX2 p.Ala74fs Pathogenic ★ 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

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-ala74 (accessed [today's date]).

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