Is MPL p.Trp435Arg (c.1303T>A) pathogenic?

MPL p.Trp435Arg (c.1303T>A) is classified Likely pathogenic in MPL (ClinVar, Single submitter, 1 submitter; last evaluated 2017-04-25). AlphaMissense: likely pathogenic (0.9622); Absent from gnomAD v4.1; Associated with congenital amegakaryocytic thrombocytopenia.

What condition is associated with MPL p.Trp435Arg (c.1303T>A)?

MPL p.Trp435Arg (c.1303T>A) is associated with congenital amegakaryocytic thrombocytopenia (ClinVar).

How common is MPL p.Trp435Arg (c.1303T>A) in the general population?

MPL p.Trp435Arg (c.1303T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MPL p.Trp435Arg (c.1303T>A)?

AlphaMissense predicts likely pathogenic (score 0.9622) — an in-silico prediction, not a clinical call.

MPL p.Trp435Arg

c.1303T>A · rs1553128241 · VCV435889

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9622 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital amegakaryocytic thrombocytopenia

Computational evidence

Protein change
AlphaMissense	0.9622	likely pathogenic ✓ concordant with ClinVar · top 1% in MPL
REVEL	0.803	moderately pathogenic-leaning
SaProt	LLR -14.27	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 5,907 bp · p 0.53 · regional, not allelic
Overall
CADD	27.2	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.Trp435Arg
Coding: c.1303T>A
MANE Select: NM_005373
dbSNP: rs1553128241
Type: single nucleotide variant
Location: chr1:43346929 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.44 · 1 PDB
Residue 435: a UniProt-annotated variant site (in camt1); the fibronectin type-iii 2 domain

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.Trp435Cys 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-trp435arg (accessed [today's date]).

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