Is MPL p.Glu230= (c.690A>G) pathogenic?

MPL p.Glu230= (c.690A>G) is classified Benign/Likely benign in MPL (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-04). Common (popmax 10.4%, afr) — too common for a highly-penetrant pathogenic allele; Associated with essential thrombocythemia.

What condition is associated with MPL p.Glu230= (c.690A>G)?

MPL p.Glu230= (c.690A>G) is associated with essential thrombocythemia, congenital amegakaryocytic thrombocytopenia (ClinVar).

How is Essential thrombocythemia inherited?

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

MPL p.Glu230=

Q: How common is MPL p.Glu230= (c.690A>G) in the general population?

MPL p.Glu230= (c.690A>G) is common (popmax 10.4%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.690A>G · rs16830693 · VCV134827

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Common

common (popmax 10.4%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

essential thrombocythemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.53	donor gain at this position · masked 0 · deltas
Constraint at this position
Conservation	phyloP 4.5	GERP 0.038, phastCons 1
Overall
CADD	8.292	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 10.4% African / African-American · 7,834/75,032 alleles

Filtering AF 10.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 10.2%

Overall 3.52% 56,878/1,614,174 alleles · common exomes 49,255/1,461,874 · genomes 7,623/152,300 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	10.4%	10
South Asian	4.77%	21
Remaining individualsnot grpmax-eligible	3.89%	26
Finnishnot grpmax-eligible	3.83%	26
Middle Eastern	3.73%	27
European (non-Finnish)	3.18%	31
East Asian	1.59%	63
Admixed American	1.53%	65
Ashkenazi Jewishnot grpmax-eligible	1.24%	81
Amishnot grpmax-eligible	0.987%	101

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.Glu230=
Coding: c.690A>G
MANE Select: NM_005373
dbSNP: rs16830693
Type: single nucleotide variant
Location: chr1:43339569 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.44 · 1 PDB
Residue 230: the fibronectin type-iii 1 domain; the 'disordered' region

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-glu230 (accessed [today's date]).

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