Is MPL p.Ala490Pro (c.1468G>C) pathogenic?

MPL p.Ala490Pro (c.1468G>C) is classified Uncertain significance in MPL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-24). AlphaMissense: likely benign (0.1553); Very rare (popmax 0.00242%, eas); Associated with essential thrombocythemia.

What condition is associated with MPL p.Ala490Pro (c.1468G>C)?

MPL p.Ala490Pro (c.1468G>C) is associated with essential thrombocythemia, congenital amegakaryocytic thrombocytopenia (ClinVar).

How common is MPL p.Ala490Pro (c.1468G>C) in the general population?

MPL p.Ala490Pro (c.1468G>C) is very rare (popmax 0.00242%, eas) (gnomAD).

How is Essential thrombocythemia inherited?

Typically Multigenic/multifactorial, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MPL p.Ala490Pro (c.1468G>C)?

AlphaMissense predicts likely benign (score 0.1553) — an in-silico prediction, not a clinical call.

MPL p.Ala490Pro

c.1468G>C · VCV4789921

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1553 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00242%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

essential thrombocythemia

Computational evidence

Protein change
AlphaMissense	0.1553	likely benign
REVEL	0.292	indeterminate
SaProt	LLR -3.64	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.66	donor loss · deltas
Pangolin	Δ0.70	loss · gain 0.24 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 5,907 bp · p 0.53 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00242% East Asian · 1/41,404 alleles

Overall 7.16e-05% 1/1,397,364 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.Ala490Pro
Coding: c.1468G>C
MANE Select: NM_005373
Type: single nucleotide variant
Location: chr1:43349002 (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

essential thrombocythemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital amegakaryocytic thrombocytopenia

For Essential thrombocythemia (Orphanet):

Inheritance: Multigenic/multifactorial, Not applicable
Onset: All ages
Prevalence: 1-5 / 10 000 (United States)

Similar variants

MPL p.Ala490fs Pathogenic ★ 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-ala490pro (accessed [today's date]).

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