Is MPL p.Ser402Pro (c.1204T>C) pathogenic?

MPL p.Ser402Pro (c.1204T>C) is classified Uncertain significance in MPL (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-12). AlphaMissense: likely benign (0.2748); Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

What condition is associated with MPL p.Ser402Pro (c.1204T>C)?

MPL p.Ser402Pro (c.1204T>C) is associated with Inborn genetic diseases (ClinVar).

How common is MPL p.Ser402Pro (c.1204T>C) in the general population?

MPL p.Ser402Pro (c.1204T>C) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about MPL p.Ser402Pro (c.1204T>C)?

AlphaMissense predicts likely benign (score 0.2748) — an in-silico prediction, not a clinical call.

MPL p.Ser402Pro

c.1204T>C · rs147608148 · VCV2306912

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2748 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2748	likely benign
REVEL	0.183	benign-leaning
SaProt	LLR -9.80	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 2.4	GERP 0.76, phastCons 1
Regional constraint	o/e 0.36	constrained · MANE · 64 bp · p 0.0013 · regional, not allelic
Overall
CADD	21.9	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 0.00134% African / African-American · 1/74,902 alleles

Overall 0.000657% 1/152,114 alleles · very rare

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.Ser402Pro
Coding: c.1204T>C
MANE Select: NM_005373
dbSNP: rs147608148
Type: single nucleotide variant
Location: chr1:43346830 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.44 · 1 PDB
Residue 402: the fibronectin type-iii 2 domain

Full MPL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MPL p.Arg462Pro Uncertain significance ★★ ⚠ same condition
MPL p.Arg464Ser Uncertain significance ★★ ⚠ same condition
MPL p.Gln186Glu Uncertain significance ★★ ⚠ same condition
MPL p.Glu160Asp Uncertain significance ★★ ⚠ same condition
MPL p.Gly270Glu Uncertain significance ★★ ⚠ same condition
MPL p.Ile385Thr Uncertain significance ★★ ⚠ same condition
MPL p.Leu582Pro Uncertain significance ★★ ⚠ same condition
MPL p.Met84Ile Uncertain significance ★★ ⚠ 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-ser402pro (accessed [today's date]).

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