Is PPM1D p.Cys346Phe (c.1037G>T) pathogenic?

PPM1D p.Cys346Phe (c.1037G>T) is classified Likely benign in PPM1D (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-10). AlphaMissense: ambiguous (0.3423); Rare (popmax 0.274%, eas); Associated with Inborn genetic diseases.

What condition is associated with PPM1D p.Cys346Phe (c.1037G>T)?

PPM1D p.Cys346Phe (c.1037G>T) is associated with Inborn genetic diseases (ClinVar).

How common is PPM1D p.Cys346Phe (c.1037G>T) in the general population?

PPM1D p.Cys346Phe (c.1037G>T) is rare (popmax 0.274%, eas) (gnomAD).

What do computational predictors say about PPM1D p.Cys346Phe (c.1037G>T)?

AlphaMissense predicts ambiguous (score 0.3423) — an in-silico prediction, not a clinical call.

PPM1D p.Cys346Phe

c.1037G>T · rs201874696 · VCV2276811

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3423 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.274%, eas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3423	ambiguous
REVEL	0.368	indeterminate
SaProt	LLR -12.55	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 8,598 bp · p 0.96 · regional, not allelic
Overall
CADD	26.2	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 0.274% East Asian · 123/44,890 alleles

Filtering AF 0.235% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.22%

Overall 0.00774% 125/1,614,150 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.274%	365
South Asian	0.0022%	45,539

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.Cys346Phe
Coding: c.1037G>T
MANE Select: NM_003620
dbSNP: rs201874696
Type: single nucleotide variant
Location: chr17:60656618 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.15 · 1 PDB
Residue 346: the ppm-type phosphatase domain; an α-helix

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-cys346phe (accessed [today's date]).

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