Is MPL p.Pro135Arg (c.404C>G) pathogenic?

MPL p.Pro135Arg (c.404C>G) is classified Conflicting classifications of pathogenicity in MPL (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-05-30). AlphaMissense: ambiguous (0.4138); Very rare (popmax 0.0011%, sas); Associated with congenital amegakaryocytic thrombocytopenia.

What condition is associated with MPL p.Pro135Arg (c.404C>G)?

MPL p.Pro135Arg (c.404C>G) is associated with congenital amegakaryocytic thrombocytopenia, essential thrombocythemia (ClinVar).

How common is MPL p.Pro135Arg (c.404C>G) in the general population?

MPL p.Pro135Arg (c.404C>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about MPL p.Pro135Arg (c.404C>G)?

AlphaMissense predicts ambiguous (score 0.4138) — an in-silico prediction, not a clinical call.

MPL p.Pro135Arg

c.404C>G · rs761623764 · VCV2924400

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4138 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

congenital amegakaryocytic thrombocytopenia

Computational evidence

Protein change
AlphaMissense	0.4138	ambiguous
REVEL	0.686	pathogenic-leaning
SaProt	LLR -12.46	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	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	25.0	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 0.0011% South Asian · 1/91,068 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,614,022 alleles · very rare exomes 3/1,461,720 · genomes 0/152,302 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,068
European (non-Finnish)	0.000169%	590,002

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.Pro135Arg
Coding: c.404C>G
MANE Select: NM_005373
dbSNP: rs761623764
Type: single nucleotide variant
Location: chr1:43339283 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.44 · 1 PDB
Residue 135: an α-helix

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.Pro135= 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
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-pro135arg (accessed [today's date]).

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