Is RUNX1 p.Asp33= (c.99T>C) pathogenic?

RUNX1 p.Asp33= (c.99T>C) is classified Uncertain significance in RUNX1 (ClinVar, Expert panel, 3 submitters; last evaluated 2024-07-25). Absent from gnomAD v4.1; Associated with hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1.

How common is RUNX1 p.Asp33= (c.99T>C) in the general population?

RUNX1 p.Asp33= (c.99T>C) is absent from gnomAD v4.1 (gnomAD).

RUNX1 p.Asp33=

Q: What condition is associated with RUNX1 p.Asp33= (c.99T>C)?

RUNX1 p.Asp33= (c.99T>C) is associated with hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 (ClinVar).

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.99T>C · rs762090330 · VCV436612

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 hematological cancer predisposition syndrome associated with RUNX1

ClinGen expert panel — Myeloid Malignancy VCEP

Uncertain Significance for hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1. Applied ACMG criteria (verbatim):

PM2_Supporting

Curation rationale (ClinGen, verbatim)

NM_001754.5(RUNX1):c.99T>C (p.Asp33=) is a synonymous variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has a SpliceAI predicted acceptor loss of 0.32, which indicates it may impact splicing (BP4/BP7 not applied). 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.

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	Δ0.32	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 9.3	GERP 1.8, phastCons 1
Overall
CADD	18.47	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.Asp33=
Coding: c.99T>C
MANE Select: NM_001754
dbSNP: rs762090330
Type: single nucleotide variant
Location: chr21:34887095 (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 hematological cancer predisposition syndrome associated with RUNX1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Inheritance: Autosomal dominant

Similar variants

RUNX1 p.Asp33Asn Uncertain significance ★★★ same residue
RUNX1 p.Asp33Tyr Uncertain significance ★★★ same residue
RUNX1 p.Asp33Glu Uncertain significance ★ same residue
RUNX1 c.351+1G>A Pathogenic ★★★ same condition
RUNX1 c.351+1G>C Likely 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-asp33 (accessed [today's date]).

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