Is RUNX1 p.Ser239= (c.717C>T) pathogenic?

RUNX1 p.Ser239= (c.717C>T) is classified Uncertain significance in RUNX1 (ClinVar, Expert panel, 3 submitters; last evaluated 2022-04-25). Absent from gnomAD v4.1; Associated with hereditary thrombocytopenia and hematologic cancer predisposition syndrome.

What condition is associated with RUNX1 p.Ser239= (c.717C>T)?

RUNX1 p.Ser239= (c.717C>T) 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.Ser239= (c.717C>T) in the general population?

RUNX1 p.Ser239= (c.717C>T) is absent from gnomAD v4.1 (gnomAD).

RUNX1 p.Ser239=

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.717C>T · rs1601415639 · VCV747644

Uncertain significance Expert panel

Classification

Uncertain significance

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

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

PM2_Supporting PP3

Curation rationale (ClinGen, verbatim)

NM_001754.5(RUNX1):c.717C>T (p.Ser239=) is a synonymous variant therefore no REVEL score and SpliceAI score donor gain 0.52 which is ≥0.38 (PP3). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PP3.

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/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.52	donor gain · deltas
Pangolin	Δ0.54	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.3	GERP 2.1, phastCons 1
Overall
CADD	19.55	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.Ser239=
Coding: c.717C>T
MANE Select: NM_001754
dbSNP: rs1601415639
Type: single nucleotide variant
Location: chr21:34834498 (GRCh38)
Gene constraint: LOEUF 0.633 · pLI 0.29 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.76 · 5 PDB
Residue 239: the 'disordered' region

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.Ser239Asn Uncertain significance ★★★ ⚠ same residue
RUNX1 p.Ser239Cys Uncertain significance ★★★ ⚠ same residue
RUNX1 p.Ser239Ile 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

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-ser239 (accessed [today's date]).

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