Is MPL p.Ala32Val (c.95C>T) pathogenic?

MPL p.Ala32Val (c.95C>T) is classified Uncertain significance in MPL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-07-03). AlphaMissense: likely benign (0.1286); Very rare (popmax 0.00223%, eas); Associated with congenital amegakaryocytic thrombocytopenia.

What condition is associated with MPL p.Ala32Val (c.95C>T)?

MPL p.Ala32Val (c.95C>T) is associated with congenital amegakaryocytic thrombocytopenia (ClinVar).

How common is MPL p.Ala32Val (c.95C>T) in the general population?

MPL p.Ala32Val (c.95C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about MPL p.Ala32Val (c.95C>T)?

AlphaMissense predicts likely benign (score 0.1286) — an in-silico prediction, not a clinical call.

MPL p.Ala32Val

c.95C>T · rs886046348 · VCV297397

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1286 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

congenital amegakaryocytic thrombocytopenia

Computational evidence

Protein change
AlphaMissense	0.1286	likely benign
REVEL	0.301	indeterminate
SaProt	LLR -9.46	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4	GERP 1.6, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 8,947 bp · p 8.9e-06 · regional, not allelic
Overall
CADD	24.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,888 alleles

Overall 0.000124% 2/1,614,092 alleles · very rare exomes 0/1,461,882 · genomes 2/152,210 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,888
African / African-American	0.00133%	74,944

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.Ala32Val
Coding: c.95C>T
MANE Select: NM_005373
dbSNP: rs886046348
Type: single nucleotide variant
Location: chr1:43338114 (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

Similar variants

MPL p.Ala32Thr Uncertain significance ★ ⚠ same residue
MPL p.Ala32= Likely benign ★ same residue
MPL p.Ala32fs 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

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-ala32val (accessed [today's date]).

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