Is MPL p.Ser585Pro (c.1753T>C) pathogenic?

MPL p.Ser585Pro (c.1753T>C) is classified Uncertain significance in MPL (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-02). AlphaMissense: likely benign (0.0728); Very rare (popmax 0.000593%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MPL p.Ser585Pro (c.1753T>C)?

MPL p.Ser585Pro (c.1753T>C) is associated with Inborn genetic diseases (ClinVar).

How common is MPL p.Ser585Pro (c.1753T>C) in the general population?

MPL p.Ser585Pro (c.1753T>C) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about MPL p.Ser585Pro (c.1753T>C)?

AlphaMissense predicts likely benign (score 0.0728) — an in-silico prediction, not a clinical call.

MPL p.Ser585Pro

c.1753T>C · rs1647101031 · VCV2367695

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0728 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0728	likely benign
REVEL	0.362	indeterminate
SaProt	LLR -6.11	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 0.96	GERP 0.38, phastCons 0.94
Regional constraint	o/e 0.96	unconstrained · MANE · 5,907 bp · p 0.53 · regional, not allelic
Overall
CADD	21.4	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 0.000593% European (non-Finnish) · 7/1,180,010 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000479% 7/1,461,892 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.Ser585Pro
Coding: c.1753T>C
MANE Select: NM_005373
dbSNP: rs1647101031
Type: single nucleotide variant
Location: chr1:43352617 (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

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-ser585pro (accessed [today's date]).

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