Is MPL p.Val556Phe (c.1666G>T) pathogenic?

MPL p.Val556Phe (c.1666G>T) is classified Conflicting classifications of pathogenicity in MPL (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.114); Ultra-rare (popmax 0.0158%, nfe); Associated with congenital amegakaryocytic thrombocytopenia.

What condition is associated with MPL p.Val556Phe (c.1666G>T)?

MPL p.Val556Phe (c.1666G>T) is associated with congenital amegakaryocytic thrombocytopenia, essential thrombocythemia, congenital amegakaryocytic thrombocytopenia 1 (ClinVar).

How common is MPL p.Val556Phe (c.1666G>T) in the general population?

MPL p.Val556Phe (c.1666G>T) is ultra-rare (popmax 0.0158%, nfe) (gnomAD).

What do computational predictors say about MPL p.Val556Phe (c.1666G>T)?

AlphaMissense predicts likely benign (score 0.114) — an in-silico prediction, not a clinical call.

MPL p.Val556Phe

c.1666G>T · rs150004498 · VCV297411

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.114 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0158%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

congenital amegakaryocytic thrombocytopenia

Computational evidence

Protein change
AlphaMissense	0.114	likely benign
REVEL	0.357	indeterminate
SaProt	LLR -6.81	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 5,907 bp · p 0.53 · regional, not allelic
Overall
CADD	14.74	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 0.0158% European (non-Finnish) · 187/1,180,030 alleles

Filtering AF 0.0139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0133%

Overall 0.0138% 222/1,614,158 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0484%	2,066
European (non-Finnish)grpmax	0.0158%	6,310
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
Admixed American	0.00333%	30,005
Remaining individualsnot grpmax-eligible	0.0016%	62,510

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val556Phe
Coding: c.1666G>T
MANE Select: NM_005373
dbSNP: rs150004498
Type: single nucleotide variant
Location: chr1:43352530 (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 congenital amegakaryocytic thrombocytopenia 1

Similar variants

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
MPL c.853+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-val556phe (accessed [today's date]).

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