Is PEX2 p.Ser175Cys (c.524C>G) pathogenic?

PEX2 p.Ser175Cys (c.524C>G) is classified Conflicting classifications of pathogenicity in PEX2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-15). AlphaMissense: likely benign (0.105); Ultra-rare (popmax 0.056%, sas); Associated with peroxisome biogenesis disorder 5A (Zellweger).

What condition is associated with PEX2 p.Ser175Cys (c.524C>G)?

PEX2 p.Ser175Cys (c.524C>G) is associated with peroxisome biogenesis disorder 5A (Zellweger) (ClinVar).

How common is PEX2 p.Ser175Cys (c.524C>G) in the general population?

PEX2 p.Ser175Cys (c.524C>G) is ultra-rare (popmax 0.056%, sas) (gnomAD).

What do computational predictors say about PEX2 p.Ser175Cys (c.524C>G)?

AlphaMissense predicts likely benign (score 0.105) — an in-silico prediction, not a clinical call.

PEX2 p.Ser175Cys

c.524C>G · rs770427885 · VCV911415

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.105 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.056%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

peroxisome biogenesis disorder 5A (Zellweger)

Computational evidence

Protein change
AlphaMissense	0.105	likely benign
REVEL	0.596	indeterminate
SaProt	LLR -7.19	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 9.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 914 bp · p 0.85 · regional, not allelic
Overall
CADD	26.2	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 0.056% South Asian · 51/91,084 alleles

Filtering AF 0.0437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0394%

Overall 0.00434% 70/1,613,944 alleles · ultra-rare exomes 66/1,461,796 · genomes 4/152,148 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.056%	1,786
Ashkenazi Jewishnot grpmax-eligible	0.0304%	3,289
Remaining individualsnot grpmax-eligible	0.0064%	15,621
European (non-Finnish)	0.000508%	196,664

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.Ser175Cys
Coding: c.524C>G
MANE Select: NM_000318
dbSNP: rs770427885
Type: single nucleotide variant
Location: chr8:76983655 (GRCh38)
Gene constraint: LOEUF 1.057 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.17
Residue 175: 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 p.Ser175fs 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
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-ser175cys (accessed [today's date]).

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