Is MPL p.Ser228Arg (c.684T>A) pathogenic?

MPL p.Ser228Arg (c.684T>A) is classified Uncertain significance in MPL (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-09-10). AlphaMissense: likely benign (0.1529); Ultra-rare (popmax 0.016%, afr); Associated with thrombocythemia 2.

What condition is associated with MPL p.Ser228Arg (c.684T>A)?

MPL p.Ser228Arg (c.684T>A) is associated with thrombocythemia 2, essential thrombocythemia, congenital amegakaryocytic thrombocytopenia (ClinVar).

How common is MPL p.Ser228Arg (c.684T>A) in the general population?

MPL p.Ser228Arg (c.684T>A) is ultra-rare (popmax 0.016%, afr) (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.Ser228Arg (c.684T>A)?

AlphaMissense predicts likely benign (score 0.1529) — an in-silico prediction, not a clinical call.

MPL p.Ser228Arg

c.684T>A · rs766536759 · VCV3048441

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1529 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thrombocythemia 2

Computational evidence

Protein change
AlphaMissense	0.1529	likely benign
REVEL	0.155	moderately benign-leaning
SaProt	LLR -7.06	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.088	GERP -0.046, phastCons 0.001
Regional constraint	o/e 0.80	unconstrained · MANE · 8,947 bp · p 8.9e-06 · regional, not allelic
Overall
CADD	10.84	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

Grpmax group 0.016% African / African-American · 12/74,928 alleles

Filtering AF 0.00921% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00722%

Overall 0.000867% 14/1,614,082 alleles · ultra-rare exomes 7/1,461,894 · genomes 7/152,188 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.016%	6,244
Admixed American	0.00167%	60,008
Remaining individualsnot grpmax-eligible	0.0016%	62,490

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.Ser228Arg
Coding: c.684T>A
MANE Select: NM_005373
dbSNP: rs766536759
Type: single nucleotide variant
Location: chr1:43339563 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.44 · 1 PDB
Residue 228: the fibronectin type-iii 1 domain; the 'disordered' region

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: essential thrombocythemia congenital amegakaryocytic thrombocytopenia

For Familial thrombocytosis (Orphanet):

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

Similar variants

MPL p.Ser228Asn Uncertain significance ★ ⚠ same residue
MPL p.Ser228= 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
MPL c.1653+1G>C 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-ser228arg (accessed [today's date]).

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