Is RUNX1 p.Pro357= (c.1071G>A) pathogenic?

RUNX1 p.Pro357= (c.1071G>A) is classified Likely benign in RUNX1 (ClinVar, Expert panel, 3 submitters; last evaluated 2024-06-24). Very rare (popmax 0.00226%, eas); Associated with hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1.

How common is RUNX1 p.Pro357= (c.1071G>A) in the general population?

RUNX1 p.Pro357= (c.1071G>A) is very rare (popmax 0.00226%, eas) (gnomAD).

RUNX1 p.Pro357=

Q: What condition is associated with RUNX1 p.Pro357= (c.1071G>A)?

RUNX1 p.Pro357= (c.1071G>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.1071G>A · rs1470891103 · VCV2146447

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00226%, 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)

This synonymous variant has a SpliceAI Δ score of 0.00 (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -0.008 (< 2)) (BP7). 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 -2.5	GERP -4.9
Overall
CADD	8.375	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00226% East Asian · 1/44,224 alleles

Overall 0.000187% 3/1,600,564 alleles · very rare exomes 3/1,448,450 · genomes 0/152,114 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00226%	44,224
Remaining individualsnot grpmax-eligible	0.00162%	61,870
South Asian	0.00113%	88,876

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.Pro357=
Coding: c.1071G>A
MANE Select: NM_001754
dbSNP: rs1470891103
Type: single nucleotide variant
Location: chr21:34792507 (GRCh38)
Gene constraint: LOEUF 0.633 · pLI 0.29 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.76 · 5 PDB
Residue 357: the 'interaction with kat6a' region; the 'interaction with kat6b' region

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.Pro357Arg Uncertain significance ★★★ same residue
RUNX1 p.Pro357Leu Uncertain significance ★★★ same residue
RUNX1 p.Pro357Ser 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-pro357 (accessed [today's date]).

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