Is MPL p.Arg102His (c.305G>A) pathogenic?

MPL p.Arg102His (c.305G>A) is classified Likely pathogenic in MPL (ClinVar, Single submitter, 2 submitters; last evaluated 2025-10-11). AlphaMissense: likely benign (0.2298); Very rare (popmax 0.00186%, nfe); Associated with congenital amegakaryocytic thrombocytopenia.

What condition is associated with MPL p.Arg102His (c.305G>A)?

MPL p.Arg102His (c.305G>A) is associated with congenital amegakaryocytic thrombocytopenia, thrombocytopenia, essential thrombocythemia (ClinVar).

How common is MPL p.Arg102His (c.305G>A) in the general population?

MPL p.Arg102His (c.305G>A) is very rare (popmax 0.00186%, nfe) (gnomAD).

What do computational predictors say about MPL p.Arg102His (c.305G>A)?

AlphaMissense predicts likely benign (score 0.2298) — an in-silico prediction, not a clinical call.

MPL p.Arg102His

c.305G>A · rs28928907 · VCV988868

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2298 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00186%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

congenital amegakaryocytic thrombocytopenia

Computational evidence

Protein change
AlphaMissense	0.2298	likely benign ⚠ discordant with ClinVar
REVEL	0.333	indeterminate
SaProt	LLR -7.50	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 8,947 bp · p 8.9e-06 · regional, not allelic
Overall
CADD	28.4	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 0.00186% European (non-Finnish) · 22/1,180,018 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00143% 23/1,614,016 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00186%	53,637
Admixed American	0.00167%	60,012

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.Arg102His
Coding: c.305G>A
MANE Select: NM_005373
dbSNP: rs28928907
Type: single nucleotide variant
Location: chr1:43338634 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.44 · 1 PDB
Residue 102: a UniProt-annotated variant site (in camt1); a UniProt-annotated variant site (in camt1; loss of function; loss of membrane localization, impaired glycosylation)

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: thrombocytopenia essential thrombocythemia

Similar variants

MPL p.Arg102Cys Pathogenic/Likely pathogenic ★★ same residue
MPL p.Arg102Pro Pathogenic ★★ ⚠ same residue
MPL p.Arg102= 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

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-arg102his (accessed [today's date]).

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