Is MPL p.Ala58Val (c.173C>T) pathogenic?

MPL p.Ala58Val (c.173C>T) is classified Conflicting classifications of pathogenicity in MPL (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-30). AlphaMissense: likely benign (0.1002); Rare (popmax 0.247%, eas); Associated with primary myelofibrosis.

What condition is associated with MPL p.Ala58Val (c.173C>T)?

MPL p.Ala58Val (c.173C>T) is associated with primary myelofibrosis, essential thrombocythemia, thrombocythemia 2 (ClinVar).

How common is MPL p.Ala58Val (c.173C>T) in the general population?

MPL p.Ala58Val (c.173C>T) is rare (popmax 0.247%, eas) (gnomAD).

How is Primary myelofibrosis inherited?

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

What do computational predictors say about MPL p.Ala58Val (c.173C>T)?

AlphaMissense predicts likely benign (score 0.1002) — an in-silico prediction, not a clinical call.

MPL p.Ala58Val

c.173C>T · rs6087 · VCV412015

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1002 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.247%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

primary myelofibrosis

Computational evidence

Protein change
AlphaMissense	0.1002	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -4.48	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 -0.094	GERP -2.6, phastCons 0.011
Regional constraint	o/e 0.80	unconstrained · MANE · 8,947 bp · p 8.9e-06 · regional, not allelic
Overall
CADD	19.56	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 0.247% East Asian · 111/44,880 alleles

Filtering AF 0.21% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.196%

Overall 0.00787% 127/1,614,152 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.247%	404
Remaining individualsnot grpmax-eligible	0.008%	12,502
African / African-American	0.004%	25,010
Admixed American	0.00167%	60,028
Finnishnot grpmax-eligible	0.00156%	64,028
European (non-Finnish)	0.000508%	196,674

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.Ala58Val
Coding: c.173C>T
MANE Select: NM_005373
dbSNP: rs6087
Type: single nucleotide variant
Location: chr1:43338192 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.44 · 1 PDB
Residue 58: a UniProt-annotated variant site (in)

Full MPL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

primary myelofibrosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: essential thrombocythemia thrombocythemia 2 congenital amegakaryocytic thrombocytopenia congenital amegakaryocytic thrombocytopenia 1

For Primary myelofibrosis (Orphanet):

Inheritance: Not applicable
Onset: Adult
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

MPL p.Ala58= 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
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-ala58val (accessed [today's date]).

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