Is PPM1D p.Asp397fs (c.1189dup) pathogenic?

PPM1D p.Asp397fs (c.1189dup) is classified Conflicting classifications of pathogenicity in PPM1D (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-07-06). 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.Asp397fs

Q: What condition is associated with PPM1D p.Asp397fs (c.1189dup)?

PPM1D p.Asp397fs (c.1189dup) is associated with intellectual developmental disorder with gastrointestinal difficulties and high pain threshold (ClinVar).

c.1189dup · VCV4715079

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

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	predicted	premature termination codon in exon 5 of 6
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -2.3	GERP -3.1

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

Variant & gene context

Gene: PPM1D
Protein: p.Asp397fs
Coding: c.1189dup
MANE Select: NM_003620
Type: Duplication
Location: chr17:60656769 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.15 · 1 PDB
Residue 397: an α-helix

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.Glu424fs Pathogenic/Likely pathogenic ★★ same condition
PPM1D p.Leu484fs Likely pathogenic ★★ same condition
PPM1D p.Met409fs Likely pathogenic ★ same condition
PPM1D p.Thr406fs Pathogenic ★ same condition
PPM1D p.Thr416fs Likely pathogenic ★ same condition
PPM1D p.Trp427fs Pathogenic ★ same condition
PPM1D p.Asn402Ter Uncertain significance ★ same condition
PPM1D p.Gly463fs 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/ppm1d-p-asp397fs (accessed [today's date]).

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