What condition is associated with MPL p.Arg426Pro (c.1277G>C)?

MPL p.Arg426Pro (c.1277G>C) is associated with congenital amegakaryocytic thrombocytopenia (ClinVar).

How common is MPL p.Arg426Pro (c.1277G>C) in the general population?

MPL p.Arg426Pro (c.1277G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MPL p.Arg426Pro (c.1277G>C)?

AlphaMissense predicts likely pathogenic (score 0.9811) — an in-silico prediction, not a clinical call.

MPL p.Arg426Pro

Q: Is MPL p.Arg426Pro (c.1277G>C) pathogenic?

MPL p.Arg426Pro (c.1277G>C) is classified Pathogenic in MPL (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely pathogenic (0.9811); Absent from gnomAD v4.1; Associated with congenital amegakaryocytic thrombocytopenia.

c.1277G>C · rs200454070 · VCV2445437

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9811 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

congenital amegakaryocytic thrombocytopenia

Computational evidence

Protein change
AlphaMissense	0.9811	likely pathogenic ✓ concordant with ClinVar · top 1% in MPL
REVEL	0.428	indeterminate
SaProt	LLR -15.66	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.24	donor loss · deltas
Constraint at this position
Conservation	phyloP 12	GERP 0.87, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 5,907 bp · p 0.53 · regional, not allelic
Overall
CADD	31.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MPL
Protein: p.Arg426Pro
Coding: c.1277G>C
MANE Select: NM_005373
dbSNP: rs200454070
Type: single nucleotide variant
Location: chr1:43346903 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.44 · 1 PDB
Residue 426: the fibronectin type-iii 2 domain; a β-strand

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

Disease context

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

Similar variants

MPL p.Arg426Ter Pathogenic/Likely pathogenic ★★ same residue
MPL p.Arg426Gln 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-arg426pro (accessed [today's date]).

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