Is MPL p.Arg102Cys (c.304C>T) pathogenic?

MPL p.Arg102Cys (c.304C>T) is classified Pathogenic/Likely pathogenic in MPL (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-11-17). AlphaMissense: ambiguous (0.5457); Ultra-rare (popmax 0.0167%, amr); Associated with congenital amegakaryocytic thrombocytopenia.

What condition is associated with MPL p.Arg102Cys (c.304C>T)?

MPL p.Arg102Cys (c.304C>T) is associated with congenital amegakaryocytic thrombocytopenia, essential thrombocythemia, congenital amegakaryocytic thrombocytopenia 1 (ClinVar).

How common is MPL p.Arg102Cys (c.304C>T) in the general population?

MPL p.Arg102Cys (c.304C>T) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about MPL p.Arg102Cys (c.304C>T)?

AlphaMissense predicts ambiguous (score 0.5457) — an in-silico prediction, not a clinical call.

MPL p.Arg102Cys

c.304C>T · rs763568293 · VCV644406

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.5457 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Conditions

congenital amegakaryocytic thrombocytopenia

Computational evidence

Protein change
AlphaMissense	0.5457	ambiguous
REVEL	0.529	indeterminate
SaProt	LLR -11.21	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	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	28.5	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 0.0167% Admixed American · 10/59,994 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.00155% 25/1,614,006 alleles · ultra-rare exomes 16/1,461,888 · genomes 9/152,118 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	5,999
Finnishnot grpmax-eligible	0.00312%	32,018
South Asian	0.0011%	91,090
European (non-Finnish)	0.00102%	98,336

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.Arg102Cys
Coding: c.304C>T
MANE Select: NM_005373
dbSNP: rs763568293
Type: single nucleotide variant
Location: chr1:43338633 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.44 · 1 PDB
Residue 102: a UniProt-annotated variant site (in camt1); a UniProt-annotated variant site (in camt1; loss of function; loss of membrane localization, impaired glycosylation)

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 congenital amegakaryocytic thrombocytopenia 1

Similar variants

MPL p.Arg102Pro Pathogenic ★★ ⚠ same residue
MPL p.Arg102His Likely pathogenic ★ ⚠ same residue
MPL p.Arg102= Likely benign ★ 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-arg102cys (accessed [today's date]).

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