Is MPL p.Arg102Pro (c.305G>C) pathogenic?

MPL p.Arg102Pro (c.305G>C) is classified Pathogenic in MPL (ClinVar, Multiple submitters, 25 submitters; last evaluated 2026-01-22). AlphaMissense: likely pathogenic (0.8371); Ultra-rare (popmax 0.0586%, nfe); Associated with thrombocythemia 2.

What condition is associated with MPL p.Arg102Pro (c.305G>C)?

MPL p.Arg102Pro (c.305G>C) is associated with thrombocythemia 2, thrombocytopenia, essential thrombocythemia (ClinVar).

How common is MPL p.Arg102Pro (c.305G>C) in the general population?

MPL p.Arg102Pro (c.305G>C) is ultra-rare (popmax 0.0586%, nfe) (gnomAD).

How is Familial thrombocytosis inherited?

Typically Autosomal dominant, X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MPL p.Arg102Pro (c.305G>C)?

AlphaMissense predicts likely pathogenic (score 0.8371) — an in-silico prediction, not a clinical call.

MPL p.Arg102Pro

c.305G>C · rs28928907 · VCV14158

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 25 submitters

AlphaMissense

likely pathogenic

0.8371 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0586%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

thrombocythemia 2

Computational evidence

Protein change
AlphaMissense	0.8371	likely pathogenic ✓ concordant with ClinVar · top 6% in MPL
REVEL	0.517	indeterminate
SaProt	LLR -8.79	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	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	27.5	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 0.0586% European (non-Finnish) · 691/1,180,008 alleles

Filtering AF 0.0549% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0535%

Overall 0.0455% 734/1,614,132 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0586%	1,708
Remaining individualsnot grpmax-eligible	0.032%	3,125
Finnishnot grpmax-eligible	0.0141%	7,115
African / African-American	0.0107%	9,378
Admixed American	0.00833%	12,006
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608

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.Arg102Pro
Coding: c.305G>C
MANE Select: NM_005373
dbSNP: rs28928907
Type: single nucleotide variant
Location: chr1:43338634 (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

thrombocythemia 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: thrombocytopenia essential thrombocythemia primary myelofibrosis long QT syndrome 2 congenital amegakaryocytic thrombocytopenia congenital amegakaryocytic thrombocytopenia 1

For Familial thrombocytosis (Orphanet):

Inheritance: Autosomal dominant, X-linked recessive
Onset: Childhood
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

MPL p.Arg102Cys Pathogenic/Likely 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-arg102pro (accessed [today's date]).

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