What condition is associated with RUNX1 p.Pro463= (c.1389C>G)?

RUNX1 p.Pro463= (c.1389C>G) is associated with hereditary thrombocytopenia and hematologic cancer predisposition syndrome, acute myeloid leukemia, hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 (ClinVar).

RUNX1 p.Pro463=

Q: Is RUNX1 p.Pro463= (c.1389C>G) pathogenic?

RUNX1 p.Pro463= (c.1389C>G) is classified Benign in RUNX1 (ClinVar, Expert panel, 13 submitters; last evaluated 2025-05-02). Common (popmax 12.4%, afr) — too common for a highly-penetrant pathogenic allele; Associated with hereditary thrombocytopenia and hematologic cancer predisposition syndrome.

Q: How common is RUNX1 p.Pro463= (c.1389C>G) in the general population?

RUNX1 p.Pro463= (c.1389C>G) is common (popmax 12.4%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is Familial platelet disorder with associated myeloid malignancy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1389C>G · rs61750222 · VCV258184

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 13 submitters

gnomAD v4.1

Common

common (popmax 12.4%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

hereditary thrombocytopenia and hematologic cancer predisposition syndrome

ClinGen expert panel — Myeloid Malignancy VCEP

Benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome. Applied ACMG criteria (verbatim):

BP7 BP4 BP2 BA1

Curation rationale (ClinGen, verbatim)

NM_001754.4(RUNX1):c.1389C>G (p.Pro463=) is a synonymous variant which has a minor allele frequency of 0.1206 (1976/16382 alleles) in the African subpopulation of the gnomAD cohort, meeting the threshold for BA1. It is detected in a homozygous state in 202 individuals in gnomAD (BP2). Splicing predictors SSF and MES indicate no significant impact on the canonical splice site, and no cryptic splice sites are created (BP4). Evolutionary conservation algorithms predict the site as not being conserved (BP7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2, BP4, BP7.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP -0.53, phastCons 1
Overall
CADD	6.182	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 12.4% African / African-American · 9,072/73,110 alleles

Filtering AF 12.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 12.1%

Overall 1.87% 28,697/1,536,470 alleles · common exomes 21,791/1,384,492 · genomes 6,906/151,978 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	12.4%	8
Ashkenazi Jewishnot grpmax-eligible	6.07%	16
Admixed American	5.13%	19
South Asian	2.9%	35
Middle Eastern	2.63%	38
Remaining individualsnot grpmax-eligible	2.38%	42
East Asian	2.3%	44
European (non-Finnish)	0.893%	112
Amishnot grpmax-eligible	0.44%	228
Finnishnot grpmax-eligible	0.175%	570

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: RUNX1
Protein: p.Pro463=
Coding: c.1389C>G
MANE Select: NM_001754
dbSNP: rs61750222
Type: single nucleotide variant
Location: chr21:34792189 (GRCh38)
Gene constraint: LOEUF 0.633 · pLI 0.29 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.76 · 5 PDB

Full RUNX1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary thrombocytopenia and hematologic cancer predisposition syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: acute myeloid leukemia hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

For Familial platelet disorder with associated myeloid malignancy (Orphanet):

Inheritance: Autosomal dominant

Similar variants

RUNX1 p.Pro463Leu Uncertain significance ★★★ ⚠ same residue
RUNX1 p.Pro463Ser Uncertain significance ★★★ ⚠ same residue
RUNX1 c.351+1G>A Pathogenic ★★★ same condition
RUNX1 c.351+1G>C Likely pathogenic ★★★ same condition
RUNX1 c.351+1G>T Pathogenic ★★★ same condition
RUNX1 c.351+2T>A Likely pathogenic ★★★ same condition
RUNX1 c.351+2T>C Likely pathogenic ★★★ same condition
RUNX1 c.352-1G>A 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/runx1-p-pro463 (accessed [today's date]).

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