Is MPL p.Arg462Pro (c.1385G>C) pathogenic?

MPL p.Arg462Pro (c.1385G>C) is classified Uncertain significance in MPL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-28). AlphaMissense: likely pathogenic (0.9821); Very rare (popmax 0.00182%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MPL p.Arg462Pro (c.1385G>C)?

MPL p.Arg462Pro (c.1385G>C) is associated with Inborn genetic diseases, essential thrombocythemia, congenital amegakaryocytic thrombocytopenia (ClinVar).

How common is MPL p.Arg462Pro (c.1385G>C) in the general population?

MPL p.Arg462Pro (c.1385G>C) is very rare (popmax 0.00182%, nfe) (gnomAD).

What do computational predictors say about MPL p.Arg462Pro (c.1385G>C)?

AlphaMissense predicts likely pathogenic (score 0.9821) — an in-silico prediction, not a clinical call.

MPL p.Arg462Pro

c.1385G>C · rs1175548872 · VCV1695380

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9821 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00182%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9821	likely pathogenic · top 1% in MPL
REVEL	0.768	pathogenic-leaning
SaProt	LLR -13.45	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 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 5,907 bp · p 0.53 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Grpmax group 0.00182% European (non-Finnish) · 21/1,150,780 alleles

Filtering AF 0.00117% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000995%

Overall 0.00141% 22/1,555,952 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00182%	54,799
Remaining individualsnot grpmax-eligible	0.00166%	60,308

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.Arg462Pro
Coding: c.1385G>C
MANE Select: NM_005373
dbSNP: rs1175548872
Type: single nucleotide variant
Location: chr1:43348919 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.44 · 1 PDB
Residue 462: the fibronectin type-iii 2 domain; a β-strand

Full MPL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: essential thrombocythemia congenital amegakaryocytic thrombocytopenia

Similar variants

MPL p.Arg462fs Likely pathogenic ★ 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-arg462pro (accessed [today's date]).

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