Is MPL p.Trp253Arg (c.757T>C) pathogenic?

MPL p.Trp253Arg (c.757T>C) is classified Uncertain significance in MPL (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-02). AlphaMissense: ambiguous (0.3986); Very rare (popmax 0.0022%, nfe); Associated with congenital amegakaryocytic thrombocytopenia 1.

What condition is associated with MPL p.Trp253Arg (c.757T>C)?

MPL p.Trp253Arg (c.757T>C) is associated with congenital amegakaryocytic thrombocytopenia 1 (ClinVar).

How common is MPL p.Trp253Arg (c.757T>C) in the general population?

MPL p.Trp253Arg (c.757T>C) is very rare (popmax 0.0022%, nfe) (gnomAD).

How is Congenital amegakaryocytic thrombocytopenia inherited?

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

What do computational predictors say about MPL p.Trp253Arg (c.757T>C)?

AlphaMissense predicts ambiguous (score 0.3986) — an in-silico prediction, not a clinical call.

MPL p.Trp253Arg

c.757T>C · rs745790969 · VCV1803236

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3986 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, nfe)

Conditions

congenital amegakaryocytic thrombocytopenia 1

Computational evidence

Protein change
AlphaMissense	0.3986	ambiguous
REVEL	0.472	indeterminate
SaProt	LLR -8.09	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.32 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.95	GERP -0.016, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 8,947 bp · p 8.9e-06 · regional, not allelic
Overall
CADD	14.67	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

Grpmax group 0.0022% European (non-Finnish) · 26/1,180,032 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00161% 26/1,614,222 alleles · very rare exomes 26/1,461,888 · genomes 0/152,334 · joint denominator

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.Trp253Arg
Coding: c.757T>C
MANE Select: NM_005373
dbSNP: rs745790969
Type: single nucleotide variant
Location: chr1:43340030 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.44 · 1 PDB
Residue 253: the fibronectin type-iii 1 domain; 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

For Congenital amegakaryocytic thrombocytopenia (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

MPL p.Trp253Ter Likely pathogenic ★ same residue
MPL c.1166-1G>C 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.981-1G>C Likely pathogenic ★★ same condition
MPL p.Arg102Cys Pathogenic/Likely pathogenic ★★ same condition
MPL p.Arg102Pro Pathogenic ★★ ⚠ same condition
MPL p.Arg257Cys 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-trp253arg (accessed [today's date]).

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