Is MPL p.Pro440= (c.1320G>C) pathogenic?

MPL p.Pro440= (c.1320G>C) is classified Likely benign in MPL (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-26). Absent from gnomAD v4.1; Associated with congenital amegakaryocytic thrombocytopenia.

What condition is associated with MPL p.Pro440= (c.1320G>C)?

MPL p.Pro440= (c.1320G>C) is associated with congenital amegakaryocytic thrombocytopenia, essential thrombocythemia (ClinVar).

How common is MPL p.Pro440= (c.1320G>C) in the general population?

MPL p.Pro440= (c.1320G>C) is absent from gnomAD v4.1 (gnomAD).

MPL p.Pro440=

c.1320G>C · rs2153919217 · VCV1127081

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

congenital amegakaryocytic thrombocytopenia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.9	GERP -3.4
Overall
CADD	7.153	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MPL
Protein: p.Pro440=
Coding: c.1320G>C
MANE Select: NM_005373
dbSNP: rs2153919217
Type: single nucleotide variant
Location: chr1:43348854 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.44 · 1 PDB
Residue 440: 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 p.Pro440Arg Uncertain significance ★ ⚠ same residue
MPL c.1165+1G>C Likely pathogenic ★★ same condition
MPL c.1166-1G>C Likely pathogenic ★★ same condition
MPL c.1468+2T>C Pathogenic/Likely pathogenic ★★ same condition
MPL c.1469-2A>T Pathogenic/Likely pathogenic ★★ same condition
MPL c.1566-1G>A Likely pathogenic ★★ same condition
MPL c.1653+1G>C Likely pathogenic ★★ same condition
MPL c.79+2T>A 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-pro440 (accessed [today's date]).

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