Is MPL p.Leu79= (c.237G>C) pathogenic?

MPL p.Leu79= (c.237G>C) is classified Likely benign in MPL (ClinVar, Single submitter, 2 submitters; last evaluated 2023-04-28). Ultra-rare (popmax 0.0143%, sas); Associated with congenital amegakaryocytic thrombocytopenia.

How common is MPL p.Leu79= (c.237G>C) in the general population?

MPL p.Leu79= (c.237G>C) is ultra-rare (popmax 0.0143%, sas) (gnomAD).

MPL p.Leu79=

Q: What condition is associated with MPL p.Leu79= (c.237G>C)?

MPL p.Leu79= (c.237G>C) is associated with congenital amegakaryocytic thrombocytopenia, essential thrombocythemia (ClinVar).

c.237G>C · rs769101640 · VCV772802

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0143%, sas)

Conditions

congenital amegakaryocytic thrombocytopenia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.70	acceptor gain · deltas
Pangolin	Δ0.24	gain · loss 0.13 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 8.6	GERP -0.19, phastCons 1
Overall
CADD	21.1	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0143% South Asian · 13/91,086 alleles

Filtering AF 0.00844% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00661%

Overall 0.000991% 16/1,614,068 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0143%	7,007
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	0.000169%	590,019

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.Leu79=
Coding: c.237G>C
MANE Select: NM_005373
dbSNP: rs769101640
Type: single nucleotide variant
Location: chr1:43338566 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.44 · 1 PDB
Residue 79: a disulfide bond; a β-strand

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.Leu79Arg Uncertain significance ★ ⚠ same residue
MPL p.Leu79fs 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

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-leu79 (accessed [today's date]).

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