Is MPL p.Gln290Pro (c.869A>C) pathogenic?

MPL p.Gln290Pro (c.869A>C) is classified Uncertain significance in MPL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-15). AlphaMissense: ambiguous (0.5079); Very rare (popmax 0.00161%, nfe); Associated with congenital amegakaryocytic thrombocytopenia 1.

What condition is associated with MPL p.Gln290Pro (c.869A>C)?

MPL p.Gln290Pro (c.869A>C) is associated with congenital amegakaryocytic thrombocytopenia 1, primary myelofibrosis, thrombocythemia 2 (ClinVar).

How common is MPL p.Gln290Pro (c.869A>C) in the general population?

MPL p.Gln290Pro (c.869A>C) is very rare (popmax 0.00161%, nfe) (gnomAD).

How is Congenital amegakaryocytic thrombocytopenia inherited?

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

What do computational predictors say about MPL p.Gln290Pro (c.869A>C)?

AlphaMissense predicts ambiguous (score 0.5079) — an in-silico prediction, not a clinical call.

MPL p.Gln290Pro

c.869A>C · VCV3891711

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5079 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Conditions

congenital amegakaryocytic thrombocytopenia 1

Computational evidence

Protein change
AlphaMissense	0.5079	ambiguous
REVEL	0.58	indeterminate
SaProt	LLR -12.94	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP 0.82, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 8,947 bp · p 8.9e-06 · regional, not allelic
Overall
CADD	19.37	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 0.00161% European (non-Finnish) · 19/1,180,032 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00118% 19/1,614,186 alleles · very rare exomes 19/1,461,886 · genomes 0/152,300 · joint denominator

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.Gln290Pro
Coding: c.869A>C
MANE Select: NM_005373
Type: single nucleotide variant
Location: chr1:43340402 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.44 · 1 PDB

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: primary myelofibrosis thrombocythemia 2

For Congenital amegakaryocytic thrombocytopenia (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

MPL p.Gln290= Likely benign ★ same residue
MPL c.1166-1G>C 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
MPL c.981-1G>C Likely pathogenic ★★ same condition
MPL p.Arg102Cys Pathogenic/Likely pathogenic ★★ same condition
MPL p.Arg102Pro 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-gln290pro (accessed [today's date]).

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