Is MPL p.Asp558fs (c.1671dup) pathogenic?

MPL p.Asp558fs (c.1671dup) is classified Pathogenic/Likely pathogenic in MPL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-05). Very rare (popmax 0.0011%, sas); Associated with congenital amegakaryocytic thrombocytopenia.

What condition is associated with MPL p.Asp558fs (c.1671dup)?

MPL p.Asp558fs (c.1671dup) is associated with congenital amegakaryocytic thrombocytopenia, essential thrombocythemia (ClinVar).

How common is MPL p.Asp558fs (c.1671dup) in the general population?

MPL p.Asp558fs (c.1671dup) is very rare (popmax 0.0011%, sas) (gnomAD).

MPL p.Asp558fs

c.1671dup · rs1647100516 · VCV1687156

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

congenital amegakaryocytic thrombocytopenia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (12 of 12) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6	GERP 0.59, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,086 alleles

Overall 0.000657% 1/152,192 alleles · very rare

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.Asp558fs
Coding: c.1671dup
MANE Select: NM_005373
dbSNP: rs1647100516
Type: Duplication
Location: chr1:43352534 (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

congenital amegakaryocytic thrombocytopenia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: essential thrombocythemia

Similar variants

MPL p.Asn250fs Pathogenic/Likely pathogenic ★★ same condition
MPL p.Gln219fs Pathogenic/Likely pathogenic ★★ same condition
MPL p.Lys140fs Pathogenic ★★ same condition
MPL p.Ser311_Gln312insHis Uncertain significance ★★ same condition
MPL c.980+1dup Likely pathogenic ★ same condition
MPL p.Ala203fs Pathogenic ★ same condition
MPL p.Ala490fs Pathogenic ★ same condition
MPL p.Glu450fs 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-asp558fs (accessed [today's date]).

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