Is PPM1D p.Arg429Ser (c.1287G>C) pathogenic?

PPM1D p.Arg429Ser (c.1287G>C) is classified Uncertain significance in PPM1D (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-12). AlphaMissense: likely benign (0.1733); Ultra-rare (popmax 0.0363%, sas).

How common is PPM1D p.Arg429Ser (c.1287G>C) in the general population?

PPM1D p.Arg429Ser (c.1287G>C) is ultra-rare (popmax 0.0363%, sas) (gnomAD).

What do computational predictors say about PPM1D p.Arg429Ser (c.1287G>C)?

AlphaMissense predicts likely benign (score 0.1733) — an in-silico prediction, not a clinical call.

PPM1D p.Arg429Ser

c.1287G>C · VCV3716119

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1733 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0363%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1733	likely benign
REVEL	0.078	moderately benign-leaning
SaProt	LLR -4.55	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 0.28	GERP -2.6, phastCons 0.095
Regional constraint	o/e 0.97	unconstrained · MANE · 6,837 bp · p 0.58 · regional, not allelic
Overall
CADD	10.97	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 0.0363% South Asian · 33/90,906 alleles

Filtering AF 0.0265% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0232%

Overall 0.00248% 40/1,611,756 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0363%	2,755
Admixed American	0.00336%	29,745
East Asian	0.00223%	44,858
Remaining individualsnot grpmax-eligible	0.0016%	62,368
European (non-Finnish)	0.000254%	392,957

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.Arg429Ser
Coding: c.1287G>C
MANE Select: NM_003620
Type: single nucleotide variant
Location: chr17:60663021 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.15 · 1 PDB
Residue 429: a UniProt-annotated variant site (in jdvs)

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

Similar variants

PPM1D p.Arg429_Val430insTer Pathogenic ★ same residue
PPM1D p.Cys407Ter Pathogenic/Likely pathogenic ★★ same type
PPM1D p.Gln404Ter Pathogenic ★★ same type
PPM1D p.Gln462Ter Likely pathogenic ★★ same type
PPM1D p.Glu423Ter Pathogenic ★★ same type
PPM1D p.Ser421Ter Pathogenic/Likely pathogenic ★★ same type
PPM1D p.Trp427Ter Pathogenic ★★ same type
PPM1D p.Arg357Cys Uncertain significance ★★ ⚠ same type

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-arg429ser (accessed [today's date]).

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