Is MPL p.Arg321Gln (c.962G>A) pathogenic?

MPL p.Arg321Gln (c.962G>A) is classified Benign/Likely benign in MPL (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0786); Low-frequency (popmax 1.54%, eas); Associated with essential thrombocythemia.

What condition is associated with MPL p.Arg321Gln (c.962G>A)?

MPL p.Arg321Gln (c.962G>A) is associated with essential thrombocythemia, congenital amegakaryocytic thrombocytopenia, congenital amegakaryocytic thrombocytopenia 1 (ClinVar).

How common is MPL p.Arg321Gln (c.962G>A) in the general population?

MPL p.Arg321Gln (c.962G>A) is low-frequency (popmax 1.54%, eas) (gnomAD).

How is Essential thrombocythemia inherited?

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

What do computational predictors say about MPL p.Arg321Gln (c.962G>A)?

AlphaMissense predicts likely benign (score 0.0786) — an in-silico prediction, not a clinical call.

MPL p.Arg321Gln

c.962G>A · rs149265851 · VCV134835

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0786 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.54%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

essential thrombocythemia

Computational evidence

Protein change
AlphaMissense	0.0786	likely benign
REVEL	0.191	benign-leaning
SaProt	LLR -6.02	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 0.56	GERP -4, phastCons 0.001
Regional constraint	o/e 0.80	unconstrained · MANE · 8,947 bp · p 8.9e-06 · regional, not allelic
Overall
CADD	10.02	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 1.54% East Asian · 692/44,876 alleles

Filtering AF 1.45% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.41%

Overall 0.0501% 808/1,614,148 alleles · low-frequency exomes 656/1,461,886 · genomes 152/152,262 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	1.54%	65
Remaining individualsnot grpmax-eligible	0.149%	672
Admixed American	0.00666%	15,006
South Asian	0.00549%	18,214
African / African-American	0.004%	25,009
European (non-Finnish)	0.000932%	107,276

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.Arg321Gln
Coding: c.962G>A
MANE Select: NM_005373
dbSNP: rs149265851
Type: single nucleotide variant
Location: chr1:43340495 (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

essential thrombocythemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital amegakaryocytic thrombocytopenia congenital amegakaryocytic thrombocytopenia 1

For Essential thrombocythemia (Orphanet):

Inheritance: Multigenic/multifactorial, Not applicable
Onset: All ages
Prevalence: 1-5 / 10 000 (United States)

Similar variants

MPL p.Arg321Trp Uncertain significance ★ ⚠ same residue
MPL p.Arg321= 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

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-arg321gln (accessed [today's date]).

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