Is MPL p.Pro133fs (c.398del) pathogenic?

MPL p.Pro133fs (c.398del) is classified Likely pathogenic in MPL (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-15). Absent from gnomAD; Associated with congenital amegakaryocytic thrombocytopenia.

What condition is associated with MPL p.Pro133fs (c.398del)?

MPL p.Pro133fs (c.398del) is associated with congenital amegakaryocytic thrombocytopenia (ClinVar).

How common is MPL p.Pro133fs (c.398del) in the general population?

MPL p.Pro133fs (c.398del) is absent from gnomAD (gnomAD).

MPL p.Pro133fs

c.398del · rs2545675638 · VCV1724582

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

congenital amegakaryocytic thrombocytopenia

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 4 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.2	GERP -1.3, phastCons 0.99

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: MPL
Protein: p.Pro133fs
Coding: c.398del
MANE Select: NM_005373
dbSNP: rs2545675638
Type: Deletion
Location: chr1:43339276 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.44 · 1 PDB
Residue 133: an α-helix

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

Disease context

congenital amegakaryocytic thrombocytopenia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MPL p.Pro133Ser Uncertain significance ★★ ⚠ same residue
MPL p.Pro133= Likely benign ★★ same residue
MPL c.1653+1del Pathogenic/Likely pathogenic ★★ same condition
MPL p.Arg325fs Pathogenic/Likely pathogenic ★★ same condition
MPL p.Cys422fs Pathogenic/Likely pathogenic ★★ same condition
MPL p.Cys77fs Pathogenic/Likely pathogenic ★★ same condition
MPL p.Glu439fs Pathogenic/Likely pathogenic ★★ same condition
MPL p.Ile138fs Pathogenic/Likely pathogenic ★★ 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/mpl-p-pro133fs (accessed [today's date]).

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