RUNX1

Chr 21ADSomatic

RUNX family transcription factor 1

Also known as: AML1, AML1-EVI-1, AMLCR1, CBF2alpha, CBFA2, EVI-1, PEBP2aB, PEBP2alpha

NCBI Gene: 861 ENSG00000159216 UniProt: Q01196 OMIM: 151385

The RUNX1 protein forms the core-binding factor (CBF) transcription complex that is essential for normal hematopoiesis and T-cell development. Mutations cause familial platelet disorder with associated myeloid malignancy and acute myeloid leukemia, inherited in an autosomal dominant pattern. The gene shows significant constraint against loss-of-function variants (LOEUF 0.438), reflecting its critical role in blood cell development.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

LOFmechanismAD/SomaticLOEUF 0.442 OMIM phenotypes

Clinical Summary— RUNX1

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Gene-Disease Validity (ClinGen)

hereditary thrombocytopenia and hematologic cancer predisposition syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.65) — some intolerance to loss-of-function variants.

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ClinVar Variants

70 unique Pathogenic / Likely Pathogenic· 224 VUS of 400 total submissions

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Clinical Trials

10 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — RUNX1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint

0.44LOEUF

pLI 0.654

Z-score 3.42

OE 0.19 (0.09–0.44)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint

2.00Z-score

OE missense 0.68 (0.61–0.77)

218 obs / 318.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios

LoF OE0.19 (0.09–0.44)

0≤0.351.4

Missense OE0.68 (0.61–0.77)

0≤0.61.4

Synonymous OE0.73

0≤1.21.6

LoF obs/exp: 4 / 20.9Missense obs/exp: 218 / 318.4Syn Z: 2.56

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveRUNX1-related platelet disorder, familial, with associated myeloid malignancyLOFAD

0.5280th %ile

GOF

0.3293th %ile

LOF

0.77top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 79% of P/LP variants are LoF · LOEUF 0.44

DN1 literature citation

Literature Evidence

DNThe myeloid transcription factor CEBPA (116897) is crucial for normal granulopoiesis, and dominant-negative mutations of the CEBPA gene are found in a significant proportion of patients with myeloblastic subtypes (M1 and M2) of AML. Pabst et al. (2001) demonstrated that the AML1-ETO fusion protein sPMID:11283671

LOFIn vitro analyses of known and novel RUNX1/AML1 mutations in dominant familial platelet disorder with predisposition to acute myelogenous leukemia: implications for mechanisms of pathogenesisPMID:11830488

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

400 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic43

Likely Pathogenic27

VUS224

Likely Benign95

Benign1

Pathogenic

Likely Pathogenic

224

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	36	0	7	0	43
Likely Pathogenic	19	7	1	0	27
VUS	7	187	18	12	224
Likely Benign	0	2	23	70	95
Benign	0	0	1	0	1
Total	62	196	50	82	390

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

RUNX1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

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GeneReview available — RUNX1

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Acute Myeloid LeukemiaRecurrent Acute Myeloid LeukemiaRefractory Acute Myeloid Leukemia

Entrectinib in Combination With ASTX727 for the Treatment of Relapsed/Refractory TP53 Mutated Acute Myeloid Leukemia

ACTIVE NOT RECRUITING

NCT05396859Phase PHASE1OHSU Knight Cancer InstituteStarted 2022-10-28

Decitabine and CedazuridineEntrectinibLaboratory Biomarker Analysis

Polycythemia VeraEssential ThrombocythaemiaMyelofibrosis

Prevalence Of Germline Gene Mutations In Patients With Myeloproliferative Neoplasms With Family History

NOT YET RECRUITING

NCT06923670Phase NAFondazione Policlinico Universitario Agostino Gemelli IRCCSStarted 2025-05-21

NGS testingNGS analysis for mutations in genes involved in familial predisposition to hematological malignancies

Bone Marrow Failure DisordersVEXAS SyndromeHemoglobinurea, Paroxysmal

Molecular and Clinical Analysis of Bone Marrow Failure: A Secondary Research Study

ENROLLING BY INVITATION

NCT07102849National Heart, Lung, and Blood Institute (NHLBI)Started 2025-09-09

Acute Myeloid Leukemia With T(8;21)(Q22;Q22)Acute Myeloid Leukemia With T(16;16)(P13;Q22)KIT Gene Mutation

A New Treatment of Newly Diagnosed KIT Mutation CBF-Acute Myeloid Leukemia

RECRUITING

NCT07028073Phase PHASE1, PHASE2The First Affiliated Hospital of Soochow UniversityStarted 2025-05-15

Group A (FIT): Avapritinib + IA regimenGroup B (UNFIT): Avapritinib + VA regimen

AML, ChildhoodAcute Myeloid Leukemia

Clinical Study of Induction Therapy Options Based on Molecular Subtyping and MRD in Children and Adolescents With AML

RECRUITING

NCT06221683Phase PHASE2Children's Hospital of Soochow UniversityStarted 2024-01-01

HomoharringtonineCytarabineEtoposide

Acute Myeloid Leukemia

IDH Targeted/Non- Targeted vs Non-targeted/IDH-targeted Approaches in the Treatment of Newly Diagnosed IDH Mutated AML Patients Not Candidates for Intensive Induction Therapy (I- DATA Study)

RECRUITING

NCT05401097Phase PHASE2Alice MimsStarted 2022-09-13

AzacitidineBiopsyEnasidenib

Inherited Bone Marrow Failure SyndromeFamilial Platelet Disorder With Predisposition to Myeloid Malignancies

Imatinib to Increase RUNX1 Activity in Participants With Germline RUNX1 Deficiency

RECRUITING

NCT06090669Phase PHASE1National Cancer Institute (NCI)Started 2023-12-19

imatinibTruSight Oncology

Inherited Hematological DiseasesRare DiseasesFPDMM

Longitudinal Studies of Patient With FPDMM

RECRUITING

NCT03854318National Human Genome Research Institute (NHGRI)Started 2019-03-28