Is RUNX1 p.Pro61= (c.183G>A) pathogenic?

RUNX1 p.Pro61= (c.183G>A) is classified Benign in RUNX1 (ClinVar, Expert panel, 8 submitters; last evaluated 2020-08-08). Low-frequency (popmax 1.46%, afr); Associated with hereditary thrombocytopenia and hematologic cancer predisposition syndrome.

What condition is associated with RUNX1 p.Pro61= (c.183G>A)?

RUNX1 p.Pro61= (c.183G>A) is associated with hereditary thrombocytopenia and hematologic cancer predisposition syndrome, acute myeloid leukemia, hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 (ClinVar).

How common is RUNX1 p.Pro61= (c.183G>A) in the general population?

RUNX1 p.Pro61= (c.183G>A) is low-frequency (popmax 1.46%, afr) (gnomAD).

RUNX1 p.Pro61=

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.183G>A · rs76558016 · VCV212088

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.46%, afr)

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):

BP4 BP2 BA1

Curation rationale (ClinGen, verbatim)

This synonymous variant is present in gnomAD (v2 and v3) at an allele frequency >0.15% with at least >5 alleles in any general continental population (BA1); in addition, the variant was found in homozygosity in the population database (BP2). Although evolutionary conservation prediction algorithms predict the site as being moderately conserved (PhyloP score: 3.03 > 0.1 [-14.1;6.4]) and the variant is not the reference nucleotide in one primate and/or three mammal species, it is predicted by SSF and MES to lead to either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created (BP4). In summary, the clinical significance of this variant is benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2, and BP4.

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 3.3	GERP 0.76, phastCons 1
Overall
CADD	14.43	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.46% African / African-American · 1,093/74,910 alleles

Filtering AF 1.39% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.36%

Overall 0.0753% 1,207/1,602,878 alleles · low-frequency exomes 578/1,450,550 · genomes 629/152,328 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.46%	69
Admixed American	0.0854%	1,171
Remaining individualsnot grpmax-eligible	0.0772%	1,296
Middle Eastern	0.0165%	6,046
European (non-Finnish)	0.00119%	84,139

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.Pro61=
Coding: c.183G>A
MANE Select: NM_001754
dbSNP: rs76558016
Type: single nucleotide variant
Location: chr21:34887011 (GRCh38)
Gene constraint: LOEUF 0.633 · pLI 0.29 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.76 · 5 PDB
Residue 61: the runt domain

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.Pro61Arg Uncertain significance ★★★ ⚠ same residue
RUNX1 p.Pro61Leu Uncertain significance ★★★ ⚠ same residue
RUNX1 p.Pro61Ser Uncertain significance ★★★ ⚠ same residue
RUNX1 p.Pro61Thr Uncertain significance ★★★ ⚠ same residue
RUNX1 p.Pro61Ala 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

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-pro61 (accessed [today's date]).

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