Is MPL p.Ser557Ala (c.1669T>G) pathogenic?

MPL p.Ser557Ala (c.1669T>G) is classified Uncertain significance in MPL (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-24). AlphaMissense: likely benign (0.0727); Very rare (popmax 0.00401%, afr); Associated with essential thrombocythemia.

What condition is associated with MPL p.Ser557Ala (c.1669T>G)?

MPL p.Ser557Ala (c.1669T>G) is associated with essential thrombocythemia, congenital amegakaryocytic thrombocytopenia (ClinVar).

How common is MPL p.Ser557Ala (c.1669T>G) in the general population?

MPL p.Ser557Ala (c.1669T>G) is very rare (popmax 0.00401%, afr) (gnomAD).

How is Essential thrombocythemia inherited?

Typically Multigenic/multifactorial, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MPL p.Ser557Ala (c.1669T>G)?

AlphaMissense predicts likely benign (score 0.0727) — an in-silico prediction, not a clinical call.

MPL p.Ser557Ala

c.1669T>G · rs142161843 · VCV2083678

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0727 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

essential thrombocythemia

Computational evidence

Protein change
AlphaMissense	0.0727	likely benign
REVEL	0.188	benign-leaning
SaProt	LLR -6.34	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 1.3	GERP 0.54, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 5,907 bp · p 0.53 · regional, not allelic
Overall
CADD	16.31	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 0.00401% African / African-American · 3/74,898 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000248% 4/1,614,028 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,966
South Asian	0.0011%	91,080

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.Ser557Ala
Coding: c.1669T>G
MANE Select: NM_005373
dbSNP: rs142161843
Type: single nucleotide variant
Location: chr1:43352533 (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

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

Also linked: congenital amegakaryocytic thrombocytopenia

For Essential thrombocythemia (Orphanet):

Inheritance: Multigenic/multifactorial, Not applicable
Onset: All ages
Prevalence: 1-5 / 10 000 (United States)

Similar variants

MPL p.Ser557Ter 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-ser557ala (accessed [today's date]).

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