Is MPL p.Arg43Ter (c.127C>T) pathogenic?

MPL p.Arg43Ter (c.127C>T) is classified Pathogenic in MPL (ClinVar, Multiple submitters, 12 submitters; last evaluated 2025-10-14). Very rare (popmax 0.00935%, afr); Associated with congenital amegakaryocytic thrombocytopenia 1.

What condition is associated with MPL p.Arg43Ter (c.127C>T)?

MPL p.Arg43Ter (c.127C>T) is associated with congenital amegakaryocytic thrombocytopenia 1, essential thrombocythemia, primary myelofibrosis (ClinVar).

How common is MPL p.Arg43Ter (c.127C>T) in the general population?

MPL p.Arg43Ter (c.127C>T) is very rare (popmax 0.00935%, afr) (gnomAD).

How is Congenital amegakaryocytic thrombocytopenia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

MPL p.Arg43Ter

c.127C>T · rs148434485 · VCV371574

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00935%, afr)

Conditions

congenital amegakaryocytic thrombocytopenia 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 12
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 2.6, phastCons 1
Overall
CADD	37.0	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 0.00935% African / African-American · 7/74,904 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.00167% 27/1,614,058 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00935%	10,701
European (non-Finnish)	0.00161%	62,108
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Arg43Ter
Coding: c.127C>T
MANE Select: NM_005373
dbSNP: rs148434485
Type: single nucleotide variant
Location: chr1:43338146 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.44 · 1 PDB
Residue 43: a disulfide bond; a β-strand

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

Disease context

congenital amegakaryocytic thrombocytopenia 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: essential thrombocythemia primary myelofibrosis thrombocythemia 2 congenital amegakaryocytic thrombocytopenia

For Congenital amegakaryocytic thrombocytopenia (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

MPL p.Arg43Gln Conflicting classifications of pathogenicity ★ ⚠ 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
MPL c.79+2T>A Pathogenic/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-arg43ter (accessed [today's date]).

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