Is MPL p.Glu439fs (c.1316_1320del) pathogenic?

MPL p.Glu439fs (c.13161320del) is classified Pathogenic/Likely pathogenic in MPL (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-08-31). Very rare (popmax 0.00275%, afr); Associated with congenital amegakaryocytic thrombocytopenia.

What condition is associated with MPL p.Glu439fs (c.1316_1320del)?

MPL p.Glu439fs (c.1316_1320del) is associated with congenital amegakaryocytic thrombocytopenia, essential thrombocythemia (ClinVar).

How common is MPL p.Glu439fs (c.1316_1320del) in the general population?

MPL p.Glu439fs (c.1316_1320del) is very rare (popmax 0.00275%, afr) (gnomAD).

MPL p.Glu439fs

c.1316_1320del · rs1292577132 · VCV1072257

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00275%, afr)

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 9 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.4	GERP 0.66, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00275% African / African-American · 2/72,802 alleles

Filtering AF 0.000456% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000171%

Overall 0.000144% 2/1,387,062 alleles · very rare

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: MPL
Protein: p.Glu439fs
Coding: c.1316_1320del
MANE Select: NM_005373
dbSNP: rs1292577132
Type: Deletion
Location: chr1:43348849 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.44 · 1 PDB
Residue 439: the fibronectin type-iii 2 domain

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

Also linked: essential thrombocythemia

Similar variants

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.Ile138fs Pathogenic/Likely pathogenic ★★ same condition
MPL p.Ile152fs Pathogenic/Likely pathogenic ★★ same condition
MPL p.Leu103fs Pathogenic/Likely pathogenic ★★ same condition
MPL p.Leu265fs 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-glu439fs (accessed [today's date]).

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