Is PEX2 p.Ser90Phe (c.269C>T) pathogenic?

PEX2 p.Ser90Phe (c.269C>T) is classified Conflicting classifications of pathogenicity in PEX2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.1207); Rare (popmax 0.228%, afr); Associated with peroxisome biogenesis disorder 5A (Zellweger).

What condition is associated with PEX2 p.Ser90Phe (c.269C>T)?

PEX2 p.Ser90Phe (c.269C>T) is associated with peroxisome biogenesis disorder 5A (Zellweger) (ClinVar).

How common is PEX2 p.Ser90Phe (c.269C>T) in the general population?

PEX2 p.Ser90Phe (c.269C>T) is rare (popmax 0.228%, afr) (gnomAD).

What do computational predictors say about PEX2 p.Ser90Phe (c.269C>T)?

AlphaMissense predicts likely benign (score 0.1207) — an in-silico prediction, not a clinical call.

PEX2 p.Ser90Phe

c.269C>T · rs146354196 · VCV167456

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1207 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.228%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

peroxisome biogenesis disorder 5A (Zellweger)

Computational evidence

Protein change
AlphaMissense	0.1207	likely benign
REVEL	0.451	indeterminate
SaProt	LLR -7.68	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP 0.67, phastCons 0.13
Regional constraint	o/e 0.99	unconstrained · MANE · 914 bp · p 0.85 · regional, not allelic
Overall
CADD	20.3	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 0.228% African / African-American · 171/75,006 alleles

Filtering AF 0.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.189%

Overall 0.012% 193/1,614,108 alleles · rare exomes 99/1,461,886 · genomes 94/152,222 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.228%	439
Remaining individualsnot grpmax-eligible	0.0192%	5,209
Admixed American	0.00833%	12,003
South Asian	0.0011%	91,082
European (non-Finnish)	0.000339%	295,004

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.Ser90Phe
Coding: c.269C>T
MANE Select: NM_000318
dbSNP: rs146354196
Type: single nucleotide variant
Location: chr8:76983910 (GRCh38)
Gene constraint: LOEUF 1.057 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.17
Residue 90: 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.Ser90Thr Uncertain significance ★ ⚠ 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-ser90phe (accessed [today's date]).

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