Is MPL p.Pro70Leu (c.209C>T) pathogenic?

MPL p.Pro70Leu (c.209C>T) is classified Likely benign in MPL (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.1487); Rare (popmax 0.107%, eas); Associated with essential thrombocythemia.

What condition is associated with MPL p.Pro70Leu (c.209C>T)?

MPL p.Pro70Leu (c.209C>T) is associated with essential thrombocythemia, congenital amegakaryocytic thrombocytopenia, congenital amegakaryocytic thrombocytopenia 1 (ClinVar).

How common is MPL p.Pro70Leu (c.209C>T) in the general population?

MPL p.Pro70Leu (c.209C>T) is rare (popmax 0.107%, 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.Pro70Leu (c.209C>T)?

AlphaMissense predicts likely benign (score 0.1487) — an in-silico prediction, not a clinical call.

MPL p.Pro70Leu

c.209C>T · rs61754776 · VCV134821

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1487 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.107%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

essential thrombocythemia

Computational evidence

Protein change
AlphaMissense	0.1487	likely benign
REVEL	0.137	moderately benign-leaning
SaProt	LLR -4.79	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.098	GERP -1.2
Regional constraint	o/e 0.80	unconstrained · MANE · 8,947 bp · p 8.9e-06 · regional, not allelic
Overall
CADD	14.74	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 0.107% East Asian · 48/44,870 alleles

Filtering AF 0.0829% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0743%

Overall 0.0292% 471/1,613,772 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.107%	935
Middle Eastern	0.0517%	1,935
Ashkenazi Jewishnot grpmax-eligible	0.0473%	2,115
European (non-Finnish)	0.0315%	3,172
Remaining individualsnot grpmax-eligible	0.0304%	3,289
African / African-American	0.008%	12,503
South Asian	0.00659%	15,178
Admixed American	0.005%	20,005

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.Pro70Leu
Coding: c.209C>T
MANE Select: NM_005373
dbSNP: rs61754776
Type: single nucleotide variant
Location: chr1:43338228 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.44 · 1 PDB
Residue 70: 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 congenital amegakaryocytic thrombocytopenia 1

For Essential thrombocythemia (Orphanet):

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

Similar variants

MPL p.Pro70= Benign/Likely benign ★★ same residue
MPL p.Pro70fs Pathogenic/Likely 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

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-pro70leu (accessed [today's date]).

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