Is MPL p.Ala58= (c.174G>A) pathogenic?

MPL p.Ala58= (c.174G>A) is classified Likely benign in MPL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-19). Very rare (popmax 0.00666%, afr); Associated with congenital amegakaryocytic thrombocytopenia.

How common is MPL p.Ala58= (c.174G>A) in the general population?

MPL p.Ala58= (c.174G>A) is very rare (popmax 0.00666%, afr) (gnomAD).

MPL p.Ala58=

Q: What condition is associated with MPL p.Ala58= (c.174G>A)?

MPL p.Ala58= (c.174G>A) is associated with congenital amegakaryocytic thrombocytopenia, essential thrombocythemia (ClinVar).

c.174G>A · rs141077413 · VCV698009

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00666%, afr)

Conditions

congenital amegakaryocytic thrombocytopenia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.2	GERP -4.1
Overall
CADD	1.14	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00666% African / African-American · 5/75,022 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.00112% 18/1,614,128 alleles · very rare exomes 15/1,461,856 · genomes 3/152,272 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00666%	15,004
East Asian	0.00446%	22,434
Admixed American	0.00167%	60,026
Remaining individualsnot grpmax-eligible	0.0016%	62,510
South Asian	0.0011%	91,078
European (non-Finnish)	0.000678%	147,504

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.Ala58=
Coding: c.174G>A
MANE Select: NM_005373
dbSNP: rs141077413
Type: single nucleotide variant
Location: chr1:43338193 (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

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

Also linked: essential thrombocythemia

Similar variants

MPL p.Ala58Val Conflicting classifications of pathogenicity ★ ⚠ 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-ala58 (accessed [today's date]).

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