Is MPL p.Pro324Arg (c.971C>G) pathogenic?

MPL p.Pro324Arg (c.971C>G) is classified Uncertain significance in MPL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely benign (0.1168); Absent from gnomAD v4.1; Associated with congenital amegakaryocytic thrombocytopenia 1.

What condition is associated with MPL p.Pro324Arg (c.971C>G)?

MPL p.Pro324Arg (c.971C>G) is associated with congenital amegakaryocytic thrombocytopenia 1 (ClinVar).

How common is MPL p.Pro324Arg (c.971C>G) in the general population?

MPL p.Pro324Arg (c.971C>G) is absent from gnomAD v4.1 (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.Pro324Arg (c.971C>G)?

AlphaMissense predicts likely benign (score 0.1168) — an in-silico prediction, not a clinical call.

MPL p.Pro324Arg

c.971C>G · VCV4278300

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1168 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

congenital amegakaryocytic thrombocytopenia 1

Computational evidence

Protein change
AlphaMissense	0.1168	likely benign
REVEL	0.365	indeterminate
SaProt	LLR -6.75	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP -0.13, phastCons 0.97
Regional constraint	o/e 0.80	unconstrained · MANE · 8,947 bp · p 8.9e-06 · regional, not allelic
Overall
CADD	21.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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.Pro324Arg
Coding: c.971C>G
MANE Select: NM_005373
Type: single nucleotide variant
Location: chr1:43340504 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.44 · 1 PDB

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.Pro324= Likely benign ★ 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-pro324arg (accessed [today's date]).

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