Is PEX5 p.Arg427Ter (c.1279C>T) pathogenic?

PEX5 p.Arg427Ter (c.1279C>T) is classified Pathogenic in PEX5 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-04-30). Very rare (popmax 0.00401%, afr); Associated with rhizomelic chondrodysplasia punctata type 5.

What condition is associated with PEX5 p.Arg427Ter (c.1279C>T)?

PEX5 p.Arg427Ter (c.1279C>T) is associated with rhizomelic chondrodysplasia punctata type 5, peroxisome biogenesis disorder 2B, peroxisome biogenesis disorder 2A (Zellweger) (ClinVar).

How common is PEX5 p.Arg427Ter (c.1279C>T) in the general population?

PEX5 p.Arg427Ter (c.1279C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

PEX5 p.Arg427Ter

c.1279C>T · rs61752137 · VCV9144

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Conditions

rhizomelic chondrodysplasia punctata type 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.15	GERP -2.8, phastCons 0.4
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00401% African / African-American · 3/74,906 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00136% 22/1,613,940 alleles · very rare exomes 19/1,461,760 · genomes 3/152,180 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,969
East Asian	0.00223%	44,892
European (non-Finnish)	0.00144%	69,408
South Asian	0.0011%	91,092

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.Arg427Ter
Coding: c.1279C>T
MANE Select: NM_001351132
dbSNP: rs61752137
Type: single nucleotide variant
Location: chr12:7208554 (GRCh38)
Gene constraint: LOEUF 0.768 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.28 · 11 PDB
Residue 427: a UniProt-annotated variant site (in pbd2b; impaired ability to mediate peroxisomal import of proteins containing both a c-terminal pts1- and pts2-type targeting signals); an α-helix

Full PEX5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

rhizomelic chondrodysplasia punctata type 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: peroxisome biogenesis disorder 2B peroxisome biogenesis disorder 2A (Zellweger)

Similar variants

PEX5 p.Arg427Gln Uncertain significance ★★ ⚠ same residue
PEX5 p.Arg427Leu Uncertain significance ★★ same residue
PEX5 p.Arg427fs Pathogenic ★ same residue
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

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-arg427ter (accessed [today's date]).

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