Is RUNX1 p.Pro49= (c.147A>G) pathogenic?

RUNX1 p.Pro49= (c.147A>G) is classified Likely benign in RUNX1 (ClinVar, Expert panel, 3 submitters; last evaluated 2024-09-18). Absent from gnomAD v4.1; Associated with hereditary thrombocytopenia and hematologic cancer predisposition syndrome.

What condition is associated with RUNX1 p.Pro49= (c.147A>G)?

RUNX1 p.Pro49= (c.147A>G) is associated with hereditary thrombocytopenia and hematologic cancer predisposition syndrome, hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 (ClinVar).

How common is RUNX1 p.Pro49= (c.147A>G) in the general population?

RUNX1 p.Pro49= (c.147A>G) is absent from gnomAD v4.1 (gnomAD).

RUNX1 p.Pro49=

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.147A>G · rs2517487878 · VCV2103402

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary thrombocytopenia and hematologic cancer predisposition syndrome

ClinGen expert panel — Myeloid Malignancy VCEP

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

PM2_Supporting BP7 BP4

Curation rationale (ClinGen, verbatim)

NM_001754.5(RUNX1):c.147A>G (p.Pro49=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.04) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.04) and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.32) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting.

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 -1.3	GERP -3.5
Overall
CADD	12.44	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RUNX1
Protein: p.Pro49=
Coding: c.147A>G
MANE Select: NM_001754
dbSNP: rs2517487878
Type: single nucleotide variant
Location: chr21:34887047 (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: 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.Pro49Ala Uncertain significance ★★★ ⚠ same residue
RUNX1 p.Pro49Leu Uncertain significance ★★★ ⚠ same residue
RUNX1 p.Pro49Ser Uncertain significance ★★★ ⚠ same residue
RUNX1 p.Pro49Thr Uncertain significance ★★★ ⚠ same residue
RUNX1 p.Pro49fs Pathogenic ★★★ 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-pro49 (accessed [today's date]).

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