Is MPL p.Arg90Ter (c.268C>T) pathogenic?

MPL p.Arg90Ter (c.268C>T) is classified Pathogenic in MPL (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-19). Very rare (popmax 0.00167%, amr); Associated with primary myelofibrosis.

What condition is associated with MPL p.Arg90Ter (c.268C>T)?

MPL p.Arg90Ter (c.268C>T) is associated with primary myelofibrosis, essential thrombocythemia, thrombocythemia 2 (ClinVar).

How common is MPL p.Arg90Ter (c.268C>T) in the general population?

MPL p.Arg90Ter (c.268C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Primary myelofibrosis inherited?

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

MPL p.Arg90Ter

c.268C>T · rs763144679 · VCV956954

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

primary myelofibrosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 12
Splicing
SpliceAI	Δ0.23	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 1.8	GERP -0.28, phastCons 0.94
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,034 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00041% 6/1,461,888 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,034
South Asian	0.0011%	91,090
European (non-Finnish)	0.000339%	295,002

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.Arg90Ter
Coding: c.268C>T
MANE Select: NM_005373
dbSNP: rs763144679
Type: single nucleotide variant
Location: chr1:43338597 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.44 · 1 PDB
Residue 90: a disulfide bond; a β-strand

Full MPL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

primary myelofibrosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: essential thrombocythemia thrombocythemia 2 congenital amegakaryocytic thrombocytopenia congenital amegakaryocytic thrombocytopenia 1

For Primary myelofibrosis (Orphanet):

Inheritance: Not applicable
Onset: Adult
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

MPL p.Arg90Gln Uncertain significance ★★ ⚠ same residue
MPL p.Arg90Pro 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-arg90ter (accessed [today's date]).

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