Is PPM1D p.Ser96Phe (c.287C>T) pathogenic?

PPM1D p.Ser96Phe (c.287C>T) is classified Uncertain significance in PPM1D (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-01). AlphaMissense: likely benign (0.2792); Very rare (popmax 0.00111%, sas); Associated with Inborn genetic diseases.

What condition is associated with PPM1D p.Ser96Phe (c.287C>T)?

PPM1D p.Ser96Phe (c.287C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PPM1D p.Ser96Phe (c.287C>T) in the general population?

PPM1D p.Ser96Phe (c.287C>T) is very rare (popmax 0.00111%, sas) (gnomAD).

What do computational predictors say about PPM1D p.Ser96Phe (c.287C>T)?

AlphaMissense predicts likely benign (score 0.2792) — an in-silico prediction, not a clinical call.

PPM1D p.Ser96Phe

c.287C>T · VCV4142596

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2792 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00111%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2792	likely benign
REVEL	0.114	moderately benign-leaning
SaProt	LLR -9.78	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 2.2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 307 bp · p 0.13 · regional, not allelic
Overall
CADD	28.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00111% South Asian · 1/90,294 alleles

Overall 0.000125% 2/1,601,150 alleles · very rare exomes 2/1,448,860 · genomes 0/152,290 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00111%	90,294
European (non-Finnish)	8.51e-05%	1,174,964

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: PPM1D
Protein: p.Ser96Phe
Coding: c.287C>T
MANE Select: NM_003620
Type: single nucleotide variant
Location: chr17:60600701 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.15 · 1 PDB
Residue 96: the ppm-type phosphatase domain; the 'interaction with chek1' region; a β-strand

Full PPM1D 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

Similar variants

PPM1D p.Gln404Ter Pathogenic ★★ same condition
PPM1D p.Arg357Cys Uncertain significance ★★ ⚠ same condition
PPM1D p.Arg582Cys Uncertain significance ★★ same condition
PPM1D p.Cys605Tyr Uncertain significance ★★ ⚠ same condition
PPM1D p.Gly60Asp Uncertain significance ★★ ⚠ same condition
PPM1D p.Ile371Met Uncertain significance ★★ ⚠ same condition
PPM1D p.Leu58Phe Uncertain significance ★★ ⚠ same condition
PPM1D p.Lys522Arg 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-ser96phe (accessed [today's date]).

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