Is MPL p.Arg464Ser (c.1392G>C) pathogenic?

MPL p.Arg464Ser (c.1392G>C) is classified Uncertain significance in MPL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-14). AlphaMissense: likely pathogenic (0.6709); Very rare (popmax 0.00192%, amr); Associated with Inborn genetic diseases.

What condition is associated with MPL p.Arg464Ser (c.1392G>C)?

MPL p.Arg464Ser (c.1392G>C) is associated with Inborn genetic diseases (ClinVar).

How common is MPL p.Arg464Ser (c.1392G>C) in the general population?

MPL p.Arg464Ser (c.1392G>C) is very rare (popmax 0.00192%, amr) (gnomAD).

What do computational predictors say about MPL p.Arg464Ser (c.1392G>C)?

AlphaMissense predicts likely pathogenic (score 0.6709) — an in-silico prediction, not a clinical call.

MPL p.Arg464Ser

c.1392G>C · VCV3397670

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6709 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00192%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6709	likely pathogenic
REVEL	0.333	indeterminate
SaProt	LLR -9.70	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 5,907 bp · p 0.53 · regional, not allelic
Overall
CADD	22.6	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 0.00192% Admixed American · 1/52,126 alleles

Filtering AF 6.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000257% 4/1,557,212 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00192%	52,126
European (non-Finnish)	0.000261%	383,857

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.Arg464Ser
Coding: c.1392G>C
MANE Select: NM_005373
Type: single nucleotide variant
Location: chr1:43348926 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.44 · 1 PDB
Residue 464: the fibronectin type-iii 2 domain; a β-strand

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.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
MPL p.Tyr328Cys 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-arg464ser (accessed [today's date]).

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