Is MPL p.Phe126fs (c.378del) pathogenic?

MPL p.Phe126fs (c.378del) is classified Pathogenic in MPL (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-01-20). Ultra-rare (popmax 0.0191%, nfe); Associated with congenital amegakaryocytic thrombocytopenia 1.

What condition is associated with MPL p.Phe126fs (c.378del)?

MPL p.Phe126fs (c.378del) is associated with congenital amegakaryocytic thrombocytopenia 1, essential thrombocythemia, primary myelofibrosis (ClinVar).

How common is MPL p.Phe126fs (c.378del) in the general population?

MPL p.Phe126fs (c.378del) is ultra-rare (popmax 0.0191%, nfe) (gnomAD).

How is Congenital amegakaryocytic thrombocytopenia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

MPL p.Phe126fs

c.378del · rs587778515 · VCV265249

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0191%, nfe)

Conditions

congenital amegakaryocytic thrombocytopenia 1

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 3 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.19	GERP -3.8, phastCons 0.11
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0191% European (non-Finnish) · 225/1,179,998 alleles

Filtering AF 0.017% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0162%

Overall 0.0142% 229/1,614,088 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0191%	5,244
Middle Eastern	0.0165%	6,062
East Asian	0.00223%	44,870
South Asian	0.0022%	45,538

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.Phe126fs
Coding: c.378del
MANE Select: NM_005373
dbSNP: rs587778515
Type: Deletion
Location: chr1:43338705 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.44 · 1 PDB
Residue 126: a β-strand

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

Disease context

congenital amegakaryocytic thrombocytopenia 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: essential thrombocythemia primary myelofibrosis thrombocythemia 2 congenital amegakaryocytic thrombocytopenia

For Congenital amegakaryocytic thrombocytopenia (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

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.Glu439fs 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

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-phe126fs (accessed [today's date]).

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