Is MPL p.Val366Ala (c.1097T>C) pathogenic?

MPL p.Val366Ala (c.1097T>C) is classified Uncertain significance in MPL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-03-30). AlphaMissense: ambiguous (0.4187); Very rare (popmax 0.00333%, amr); Associated with essential thrombocythemia.

What condition is associated with MPL p.Val366Ala (c.1097T>C)?

MPL p.Val366Ala (c.1097T>C) is associated with essential thrombocythemia, congenital amegakaryocytic thrombocytopenia (ClinVar).

How common is MPL p.Val366Ala (c.1097T>C) in the general population?

MPL p.Val366Ala (c.1097T>C) is very rare (popmax 0.00333%, amr) (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.Val366Ala (c.1097T>C)?

AlphaMissense predicts ambiguous (score 0.4187) — an in-silico prediction, not a clinical call.

MPL p.Val366Ala

c.1097T>C · VCV3762904

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4187 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

essential thrombocythemia

Computational evidence

Protein change
AlphaMissense	0.4187	ambiguous
REVEL	0.674	pathogenic-leaning
SaProt	LLR -9.56	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 8,947 bp · p 8.9e-06 · regional, not allelic
Overall
CADD	25.5	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 0.00333% Admixed American · 2/60,020 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000137% 2/1,461,884 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.Val366Ala
Coding: c.1097T>C
MANE Select: NM_005373
Type: single nucleotide variant
Location: chr1:43346561 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.44 · 1 PDB
Residue 366: 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 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
MPL c.853+1G>A 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-val366ala (accessed [today's date]).

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