MPL p.Thr421Pro
c.1261A>C · VCV4791615
Uncertain significance
Single submitter
Classification
Uncertain significance
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
AlphaMissense
ambiguous
0.533 · ACMG-weighted
gnomAD v4.1
Absent
absent from gnomAD v4.1
Missense predictors
2/2 damaging
REVEL, SaProt · AlphaMissense indeterminate
Conditions
2
congenital amegakaryocytic thrombocytopenia
Computational evidence
| Protein change | ||
| AlphaMissense | 0.533 | ambiguous |
|---|---|---|
| REVEL | 0.644 | pathogenic-leaning |
| SaProt | LLR -14.79 | damaging |
| ⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 11 | GERP 1.9, phastCons 1 |
| Regional constraint | o/e 0.96 | unconstrained · MANE · 5,907 bp · p 0.53 · regional, not allelic |
| Overall | ||
| CADD | 26.0 | 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.Thr421Pro
- Coding
- c.1261A>C
- MANE Select
- NM_005373
- Type
- single nucleotide variant
- Location
- chr1:43346887 (GRCh38)
- Gene constraint
- LOEUF 1.022 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 73.44 · 1 PDB
- Residue 421
- the fibronectin type-iii 2 domain; a β-strand
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-thr421pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown