What condition is associated with PEX5 p.Phe218Ser (c.653T>C)?

PEX5 p.Phe218Ser (c.653T>C) is associated with rhizomelic chondrodysplasia punctata type 5 (ClinVar).

How common is PEX5 p.Phe218Ser (c.653T>C) in the general population?

PEX5 p.Phe218Ser (c.653T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PEX5 p.Phe218Ser (c.653T>C)?

AlphaMissense predicts likely pathogenic (score 0.9936) — an in-silico prediction, not a clinical call.

PEX5 p.Phe218Ser

Q: Is PEX5 p.Phe218Ser (c.653T>C) pathogenic?

PEX5 p.Phe218Ser (c.653T>C) is classified Pathogenic in PEX5 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely pathogenic (0.9936); Absent from gnomAD v4.1; Associated with rhizomelic chondrodysplasia punctata type 5.

c.653T>C · VCV4530662

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9936 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

rhizomelic chondrodysplasia punctata type 5

Computational evidence

Protein change
AlphaMissense	0.9936	likely pathogenic ✓ concordant with ClinVar · top 5% in PEX5
REVEL	0.834	moderately pathogenic-leaning
SaProt	LLR -12.03	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.7, phastCons 1
Overall
CADD	29.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PEX5
Protein: p.Phe218Ser
Coding: c.653T>C
MANE Select: NM_001351132
Type: single nucleotide variant
Location: chr12:7202251 (GRCh38)
Gene constraint: LOEUF 0.768 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.28 · 11 PDB
Residue 218: a UniProt-annotated variant site (found in a family with congenital cataract; likely pathogenic; impaired interaction with pex7; impaired ability to mediate peroxisomal import of proteins containing a c-terminal pts2-type targeting signal without affecting import of proteins with a pts1 targeting signal)

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

Similar variants

PEX5 p.Phe218Leu Uncertain significance ★ ⚠ same residue
PEX5 p.Phe218= Likely benign ★ same residue
PEX5 c.967-1G>A Likely pathogenic ★★ same condition
PEX5 p.Arg420Ter Pathogenic ★★ same condition
PEX5 p.Arg427Ter Pathogenic ★★ same condition
PEX5 p.Asn526Lys Pathogenic/Likely pathogenic ★★ same condition
PEX5 p.Trp184Ter Pathogenic/Likely pathogenic ★★ same condition
PEX5 p.Arg77His Uncertain significance ★★ ⚠ 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-phe218ser (accessed [today's date]).

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