Is RUNX1 p.Arg166= (c.496C>A) pathogenic?

RUNX1 p.Arg166= (c.496C>A) is classified Likely benign in RUNX1 (ClinVar, Expert panel, 3 submitters; last evaluated 2022-08-23). Very rare (popmax 0.00446%, eas); Associated with hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1.

How common is RUNX1 p.Arg166= (c.496C>A) in the general population?

RUNX1 p.Arg166= (c.496C>A) is very rare (popmax 0.00446%, eas) (gnomAD).

RUNX1 p.Arg166=

Q: What condition is associated with RUNX1 p.Arg166= (c.496C>A)?

RUNX1 p.Arg166= (c.496C>A) 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.496C>A · rs759068561 · VCV570036

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

ClinGen expert panel — Myeloid Malignancy VCEP

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

BP7 BP4

Curation rationale (ClinGen, verbatim)

NM_001754.5(RUNX1):c.496C>A (p.Arg166=) is a synonymous variant. Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 1.6 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). Synonymous variant therefore no REVEL score and SpliceAI is ≤ 0.20 (0.14) (BP4). 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.

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 6.4	GERP 0.025, phastCons 1
Overall
CADD	14.57	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,868 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000124% 2/1,613,890 alleles · very rare exomes 2/1,461,770 · genomes 0/152,120 · joint denominator

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.Arg166=
Coding: c.496C>A
MANE Select: NM_001754
dbSNP: rs759068561
Type: single nucleotide variant
Location: chr21:34880569 (GRCh38)
Gene constraint: LOEUF 0.633 · pLI 0.29 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.76 · 5 PDB
Residue 166: the runt domain; a β-strand

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.Arg166Gln Pathogenic ★★★ same residue
RUNX1 p.Arg166Ter Pathogenic ★★★ same residue
RUNX1 p.Arg166Leu Likely pathogenic ★★ same residue
RUNX1 p.Arg166Pro 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

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-arg166 (accessed [today's date]).

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