Is MPL p.Phe104Ser (c.311T>C) pathogenic?

MPL p.Phe104Ser (c.311T>C) is classified Likely pathogenic in MPL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-17). AlphaMissense: likely pathogenic (0.838); Very rare (popmax 0.00267%, afr); Associated with congenital amegakaryocytic thrombocytopenia.

What condition is associated with MPL p.Phe104Ser (c.311T>C)?

MPL p.Phe104Ser (c.311T>C) is associated with congenital amegakaryocytic thrombocytopenia, essential thrombocythemia, primary myelofibrosis (ClinVar).

How common is MPL p.Phe104Ser (c.311T>C) in the general population?

MPL p.Phe104Ser (c.311T>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about MPL p.Phe104Ser (c.311T>C)?

AlphaMissense predicts likely pathogenic (score 0.838) — an in-silico prediction, not a clinical call.

MPL p.Phe104Ser

c.311T>C · rs1196161699 · VCV653595

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.838 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital amegakaryocytic thrombocytopenia

Computational evidence

Protein change
AlphaMissense	0.838	likely pathogenic ✓ concordant with ClinVar · top 6% in MPL
REVEL	0.775	moderately pathogenic-leaning
SaProt	LLR -10.23	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	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	26.5	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 0.00267% African / African-American · 2/74,884 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,613,990 alleles · very rare exomes 1/1,461,890 · genomes 1/152,100 · joint denominator

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.Phe104Ser
Coding: c.311T>C
MANE Select: NM_005373
dbSNP: rs1196161699
Type: single nucleotide variant
Location: chr1:43338640 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.44 · 1 PDB
Residue 104: a UniProt-annotated variant site (in camt1; loss of function)

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

Disease context

congenital amegakaryocytic thrombocytopenia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: essential thrombocythemia primary myelofibrosis thrombocythemia 2 congenital amegakaryocytic thrombocytopenia 1

Similar variants

MPL p.Phe104fs Pathogenic/Likely pathogenic ★★ same residue
MPL c.1165+1G>C Likely pathogenic ★★ same condition
MPL c.1166-1G>C Likely pathogenic ★★ same condition
MPL c.1468+2T>C Pathogenic/Likely pathogenic ★★ same condition
MPL c.1469-2A>T Pathogenic/Likely pathogenic ★★ same condition
MPL c.1566-1G>A Likely pathogenic ★★ same condition
MPL c.1653+1G>C Likely pathogenic ★★ same condition
MPL c.79+2T>A Pathogenic/Likely pathogenic ★★ 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-phe104ser (accessed [today's date]).

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