Is PPM1D p.Phe445Ile (c.1333T>A) pathogenic?

PPM1D p.Phe445Ile (c.1333T>A) is classified Likely benign in PPM1D (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-13). AlphaMissense: likely benign (0.0888); Very rare (popmax 0.000593%, nfe).

How common is PPM1D p.Phe445Ile (c.1333T>A) in the general population?

PPM1D p.Phe445Ile (c.1333T>A) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about PPM1D p.Phe445Ile (c.1333T>A)?

AlphaMissense predicts likely benign (score 0.0888) — an in-silico prediction, not a clinical call.

PPM1D p.Phe445Ile

c.1333T>A · rs2143731383 · VCV2818979

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0888 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0888	likely benign
REVEL	0.07	moderately benign-leaning
SaProt	LLR -5.50	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 4.2	GERP -0.3, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 6,837 bp · p 0.58 · regional, not allelic
Overall
CADD	17.69	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

Grpmax group 0.000593% European (non-Finnish) · 7/1,179,964 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,614,134 alleles · very rare exomes 7/1,461,804 · genomes 0/152,330 · joint denominator

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.Phe445Ile
Coding: c.1333T>A
MANE Select: NM_003620
dbSNP: rs2143731383
Type: single nucleotide variant
Location: chr17:60663067 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.15 · 1 PDB
Residue 445: a UniProt-annotated variant site (in jdvs)

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

Similar variants

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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
PPM1D p.Arg557Ter 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-phe445ile (accessed [today's date]).

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