Is MPL p.Ser505Arg (c.1513A>C) pathogenic?

MPL p.Ser505Arg (c.1513A>C) is classified Uncertain significance in MPL (ClinVar, Single submitter, 1 submitter; last evaluated 2017-04-18). AlphaMissense: likely pathogenic (0.9581); Absent from gnomAD v4.1.

How common is MPL p.Ser505Arg (c.1513A>C) in the general population?

MPL p.Ser505Arg (c.1513A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MPL p.Ser505Arg (c.1513A>C)?

AlphaMissense predicts likely pathogenic (score 0.9581) — an in-silico prediction, not a clinical call.

MPL p.Ser505Arg

c.1513A>C · rs1057519752 · VCV435888

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9581 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9581	likely pathogenic · top 2% in MPL
REVEL	0.399	indeterminate
SaProt	LLR -10.89	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 5,907 bp · p 0.53 · regional, not allelic
Overall
CADD	21.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MPL
Protein: p.Ser505Arg
Coding: c.1513A>C
MANE Select: NM_005373
dbSNP: rs1057519752
Type: single nucleotide variant
Location: chr1:43349307 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.44 · 1 PDB
Residue 505: a UniProt-annotated variant site (in thcyt2; activating mutation; induces mpl autonomous dimerization and signal activation in the absence of the ligand)

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

Similar variants

MPL p.Ser505Asn Pathogenic ★★ ⚠ same residue
MPL p.Ser505= Likely benign ★ same residue
MPL c.1165+1G>C Likely pathogenic ★★ same type
MPL c.1166-1G>C Likely pathogenic ★★ same type
MPL c.1468+2T>C Pathogenic/Likely pathogenic ★★ same type
MPL c.1469-2A>T Pathogenic/Likely pathogenic ★★ same type
MPL c.1566-1G>A Likely pathogenic ★★ same type
MPL c.1653+1G>C Likely pathogenic ★★ same type

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-ser505arg (accessed [today's date]).

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