Is PPM1D p.Ile486fs (c.1455del) pathogenic?

PPM1D p.Ile486fs (c.1455del) is classified Pathogenic in PPM1D (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-02). Associated with intellectual developmental disorder with gastrointestinal difficulties and high pain threshold.

How is Jansen-de Vries syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

PPM1D p.Ile486fs

Q: What condition is associated with PPM1D p.Ile486fs (c.1455del)?

PPM1D p.Ile486fs (c.1455del) is associated with intellectual developmental disorder with gastrointestinal difficulties and high pain threshold (ClinVar).

c.1455del · VCV4688060

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

intellectual developmental disorder with gastrointestinal difficulties and high pain threshold

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (6 of 6) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9	GERP 2.3, phastCons 1

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

Variant & gene context

Gene: PPM1D
Protein: p.Ile486fs
Coding: c.1455del
MANE Select: NM_003620
Type: Deletion
Location: chr17:60663188 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.15 · 1 PDB
Residue 486: a UniProt-annotated variant site (in jdvs); a UniProt-annotated variant site (in oc; may be associated with disease susceptibility); a UniProt-annotated variant site (in bc; may be associated with disease susceptibility; gain-of-function mutation that results in increased negative regulation of p53 expression in response to ionizing radiation exposure); a UniProt-annotated variant site (in bc; may be associated with disease susceptibility)

Full PPM1D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual developmental disorder with gastrointestinal difficulties and high pain threshold — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Jansen-de Vries syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy

Similar variants

PPM1D p.Arg536fs Likely pathogenic ★★ same condition
PPM1D p.Pro413fs Likely pathogenic ★★ same condition
PPM1D p.Tyr401fs Pathogenic/Likely pathogenic ★★ same condition
PPM1D p.Arg429_Val430insTer Pathogenic ★ same condition
PPM1D p.Asn431_Ser432insTer Likely pathogenic ★ same condition
PPM1D p.Pro471fs Likely pathogenic ★ same condition
PPM1D p.Pro518fs Likely pathogenic ★ same condition
PPM1D p.Ser503fs 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/ppm1d-p-ile486fs (accessed [today's date]).

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