Is MPL p.Pro133Ser (c.397C>T) pathogenic?

MPL p.Pro133Ser (c.397C>T) is classified Uncertain significance in MPL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-11). AlphaMissense: likely pathogenic (0.6975); Absent from gnomAD v4.1; Associated with congenital amegakaryocytic thrombocytopenia.

What condition is associated with MPL p.Pro133Ser (c.397C>T)?

MPL p.Pro133Ser (c.397C>T) is associated with congenital amegakaryocytic thrombocytopenia, essential thrombocythemia (ClinVar).

How common is MPL p.Pro133Ser (c.397C>T) in the general population?

MPL p.Pro133Ser (c.397C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MPL p.Pro133Ser (c.397C>T)?

AlphaMissense predicts likely pathogenic (score 0.6975) — an in-silico prediction, not a clinical call.

MPL p.Pro133Ser

c.397C>T · rs2153916679 · VCV2581054

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6975 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

congenital amegakaryocytic thrombocytopenia

Computational evidence

Protein change
AlphaMissense	0.6975	likely pathogenic
REVEL	0.55	indeterminate
SaProt	LLR -9.13	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 8,947 bp · p 8.9e-06 · regional, not allelic
Overall
CADD	21.0	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.Pro133Ser
Coding: c.397C>T
MANE Select: NM_005373
dbSNP: rs2153916679
Type: single nucleotide variant
Location: chr1:43339276 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.44 · 1 PDB
Residue 133: an α-helix

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

Also linked: essential thrombocythemia

Similar variants

MPL p.Pro133= Likely benign ★★ same residue
MPL p.Pro133fs Likely pathogenic ★ same residue
MPL p.Pro133Leu 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

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-pro133ser (accessed [today's date]).

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