Is PEX5 p.Glu65Asp (c.195A>C) pathogenic?

PEX5 p.Glu65Asp (c.195A>C) is classified Uncertain significance in PEX5 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-07-05). AlphaMissense: ambiguous (0.4205); Ultra-rare (popmax 0.024%, afr); Associated with Inborn genetic diseases.

What condition is associated with PEX5 p.Glu65Asp (c.195A>C)?

PEX5 p.Glu65Asp (c.195A>C) is associated with Inborn genetic diseases, peroxisome biogenesis disorder 2B (ClinVar).

How common is PEX5 p.Glu65Asp (c.195A>C) in the general population?

PEX5 p.Glu65Asp (c.195A>C) is ultra-rare (popmax 0.024%, afr) (gnomAD).

What do computational predictors say about PEX5 p.Glu65Asp (c.195A>C)?

AlphaMissense predicts ambiguous (score 0.4205) — an in-silico prediction, not a clinical call.

PEX5 p.Glu65Asp

c.195A>C · rs147730752 · VCV598356

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4205 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.024%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4205	ambiguous
REVEL	0.571	indeterminate
SaProt	LLR -7.09	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.7	GERP -2.1, phastCons 1
Overall
CADD	21.7	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 0.024% African / African-American · 18/74,890 alleles

Filtering AF 0.0155% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0128%

Overall 0.00118% 19/1,614,014 alleles · ultra-rare exomes 6/1,461,888 · genomes 13/152,126 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.024%	4,161
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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: PEX5
Protein: p.Glu65Asp
Coding: c.195A>C
MANE Select: NM_001351132
dbSNP: rs147730752
Type: single nucleotide variant
Location: chr12:7191237 (GRCh38)
Gene constraint: LOEUF 0.768 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.28 · 11 PDB
Residue 65: an α-helix

Full PEX5 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 2B

Similar variants

PEX5 c.449-2A>G Pathogenic/Likely pathogenic ★★ same condition
PEX5 c.552-1G>A Pathogenic/Likely pathogenic ★★ same condition
PEX5 c.847-2A>G Likely pathogenic ★★ same condition
PEX5 c.967-1G>A Likely pathogenic ★★ same condition
PEX5 p.Arg237Ter Pathogenic/Likely pathogenic ★★ same condition
PEX5 p.Arg276Ter Pathogenic/Likely pathogenic ★★ same condition
PEX5 p.Arg420Ter Pathogenic ★★ same condition
PEX5 p.Arg427Ter 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/pex5-p-glu65asp (accessed [today's date]).

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