Is PEX2 p.Arg51His (c.152G>A) pathogenic?

PEX2 p.Arg51His (c.152G>A) is classified Uncertain significance in PEX2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-09-01). AlphaMissense: likely benign (0.0686); Ultra-rare (popmax 0.045%, amr); Associated with Inborn genetic diseases.

What condition is associated with PEX2 p.Arg51His (c.152G>A)?

PEX2 p.Arg51His (c.152G>A) is associated with Inborn genetic diseases, peroxisome biogenesis disorder 5A (Zellweger), Zellweger spectrum disorders (ClinVar).

How common is PEX2 p.Arg51His (c.152G>A) in the general population?

PEX2 p.Arg51His (c.152G>A) is ultra-rare (popmax 0.045%, amr) (gnomAD).

What do computational predictors say about PEX2 p.Arg51His (c.152G>A)?

AlphaMissense predicts likely benign (score 0.0686) — an in-silico prediction, not a clinical call.

PEX2 p.Arg51His

c.152G>A · rs549242503 · VCV1025622

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0686 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.045%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0686	likely benign
REVEL	0.107	moderately benign-leaning
SaProt	LLR -8.31	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 -0.49	GERP -1.6, phastCons 0.02
Regional constraint	o/e 0.99	unconstrained · MANE · 914 bp · p 0.85 · regional, not allelic
Overall
CADD	15.5	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 0.045% Admixed American · 27/59,958 alleles

Filtering AF 0.0317% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0273%

Overall 0.00335% 54/1,613,468 alleles · ultra-rare exomes 40/1,461,188 · genomes 14/152,280 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.045%	2,221
African / African-American	0.0107%	9,372
Remaining individualsnot grpmax-eligible	0.0032%	31,232
East Asian	0.00223%	44,888
European (non-Finnish)	0.00136%	73,723

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.Arg51His
Coding: c.152G>A
MANE Select: NM_000318
dbSNP: rs549242503
Type: single nucleotide variant
Location: chr8:76984027 (GRCh38)
Gene constraint: LOEUF 1.057 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.17
Residue 51: a UniProt-annotated variant site (in pbd5a)

Full PEX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: peroxisome biogenesis disorder 5A (Zellweger)Zellweger spectrum disorders

Similar variants

PEX2 p.Arg51Cys Uncertain significance ★★ ⚠ same residue
PEX2 p.Arg51Leu 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

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-arg51his (accessed [today's date]).

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