Is MPL p.Pro133Leu (c.398C>T) pathogenic?

MPL p.Pro133Leu (c.398C>T) is classified Uncertain significance in MPL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-26). AlphaMissense: likely benign (0.3133); Ultra-rare (popmax 0.017%, mid).

How common is MPL p.Pro133Leu (c.398C>T) in the general population?

MPL p.Pro133Leu (c.398C>T) is ultra-rare (popmax 0.017%, mid) (gnomAD).

What do computational predictors say about MPL p.Pro133Leu (c.398C>T)?

AlphaMissense predicts likely benign (score 0.3133) — an in-silico prediction, not a clinical call.

MPL p.Pro133Leu

c.398C>T · rs371227552 · VCV2577053

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3133 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.017%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.3133	likely benign
REVEL	0.54	indeterminate
SaProt	LLR -4.14	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL 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	21.7	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 0.017% Middle Eastern · 1/5,886 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000992% 16/1,613,710 alleles · ultra-rare exomes 12/1,461,558 · genomes 4/152,152 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.017%	5,886
South Asian	0.0022%	45,530
Admixed American	0.00167%	60,008
Remaining individualsnot grpmax-eligible	0.0016%	62,436
African / African-American	0.00133%	74,916
European (non-Finnish)	0.000847%	117,998

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.Pro133Leu
Coding: c.398C>T
MANE Select: NM_005373
dbSNP: rs371227552
Type: single nucleotide variant
Location: chr1:43339277 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.44 · 1 PDB
Residue 133: an α-helix

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

Similar variants

MPL p.Pro133Ser Uncertain significance ★★ ⚠ same residue
MPL p.Pro133= Likely benign ★★ same residue
MPL p.Pro133fs Likely pathogenic ★ 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

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-pro133leu (accessed [today's date]).

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