Is RUNX1 p.Ala142= (c.426T>C) pathogenic?

RUNX1 p.Ala142= (c.426T>C) is classified Likely benign in RUNX1 (ClinVar, Expert panel, 3 submitters; last evaluated 2022-07-05). Very rare (popmax 0.00333%, amr); Associated with hereditary thrombocytopenia and hematologic cancer predisposition syndrome.

What condition is associated with RUNX1 p.Ala142= (c.426T>C)?

RUNX1 p.Ala142= (c.426T>C) 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.Ala142= (c.426T>C) in the general population?

RUNX1 p.Ala142= (c.426T>C) is very rare (popmax 0.00333%, amr) (gnomAD).

RUNX1 p.Ala142=

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.426T>C · rs779032088 · VCV1142251

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

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):

BP7 BP4

Curation rationale (ClinGen, verbatim)

NM_001754.5(RUNX1):c.426T>C (p.Ala142=) is a synonymous variant therefore REVEL score is not applicable and SpliceAI is ≤0.20 (0.00) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -2.86813 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). In summary, this variant meets the criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 and 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 looked up on this page · why
Constraint at this position
Conservation	phyloP -11	GERP -4.1
Overall
CADD	0.075	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/59,998 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000372% 6/1,614,070 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,999
European (non-Finnish)	0.000339%	295,009

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.Ala142=
Coding: c.426T>C
dbSNP: rs779032088
Type: single nucleotide variant
Location: chr21:34880639 (GRCh38)

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

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-ala142 (accessed [today's date]).

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