Is MPL p.Ala463Val (c.1388C>T) pathogenic?

MPL p.Ala463Val (c.1388C>T) is classified Uncertain significance in MPL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-22). AlphaMissense: ambiguous (0.3808); Absent from gnomAD v4.1; Associated with essential thrombocythemia.

What condition is associated with MPL p.Ala463Val (c.1388C>T)?

MPL p.Ala463Val (c.1388C>T) is associated with essential thrombocythemia, congenital amegakaryocytic thrombocytopenia (ClinVar).

How common is MPL p.Ala463Val (c.1388C>T) in the general population?

MPL p.Ala463Val (c.1388C>T) is absent from gnomAD v4.1 (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.Ala463Val (c.1388C>T)?

AlphaMissense predicts ambiguous (score 0.3808) — an in-silico prediction, not a clinical call.

MPL p.Ala463Val

c.1388C>T · VCV4789927

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3808 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,556,690)

Conditions

essential thrombocythemia

Computational evidence

Protein change
AlphaMissense	0.3808	ambiguous
REVEL	0.405	indeterminate
SaProt	LLR -8.62	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 5,907 bp · p 0.53 · regional, not allelic
Overall
CADD	25.4	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

No allele count reported in gnomAD v4.1 (AN 1,556,690). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: MPL
Protein: p.Ala463Val
Coding: c.1388C>T
MANE Select: NM_005373
Type: single nucleotide variant
Location: chr1:43348922 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.44 · 1 PDB
Residue 463: the fibronectin type-iii 2 domain; a β-strand

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.Ala463= Likely benign ★ same residue
MPL p.Ala463Gly 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

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-ala463val (accessed [today's date]).

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