Is RUNX1 p.Arg346Pro (c.1037G>C) pathogenic?

RUNX1 p.Arg346Pro (c.1037G>C) is classified Uncertain significance in RUNX1 (ClinVar, Expert panel, 2 submitters; last evaluated 2024-08-01). AlphaMissense: likely pathogenic (0.919); Absent from gnomAD v4.1; Associated with hereditary thrombocytopenia and hematologic cancer predisposition syndrome.

What condition is associated with RUNX1 p.Arg346Pro (c.1037G>C)?

RUNX1 p.Arg346Pro (c.1037G>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.Arg346Pro (c.1037G>C) in the general population?

RUNX1 p.Arg346Pro (c.1037G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RUNX1 p.Arg346Pro (c.1037G>C)?

AlphaMissense predicts likely pathogenic (score 0.919) — an in-silico prediction, not a clinical call.

RUNX1 p.Arg346Pro

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.1037G>C · rs1282562937 · VCV1999266

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.919 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

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

Curation rationale (ClinGen, verbatim)

NM_001754.5(RUNX1):c.1037G>C (p.Arg346Pro) is a missense variant which is absent from gnomAD v2 and v3 (PM2_Supporting). The computational predictor REVEL gives a score of 0.666, which is neither above nor below the thresholds predicting a damaging or benign impact on RUNX1 function, but the splice site predictor SpliceAI indicated that the variant has no impact on splicing. In summary, this variant meets the criteria to be classified as a VUS for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM2_Supporting.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.919	likely pathogenic
REVEL	0.666	pathogenic-leaning
SaProt	LLR -8.50	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.7, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 42 kb · p 0.0085 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R319P vs ClinVar R346P) — verify the residue.

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.Arg346Pro
Coding: c.1037G>C
MANE Select: NM_001754
dbSNP: rs1282562937
Type: single nucleotide variant
Location: chr21:34792541 (GRCh38)
Gene constraint: LOEUF 0.633 · pLI 0.29 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.76 · 5 PDB
Residue 319 UniProt numbering: 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 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.Arg346Cys Uncertain significance ★★★ ⚠ same residue
RUNX1 p.Arg346His Uncertain significance ★★★ same residue
RUNX1 p.Arg346= Likely benign ★★★ same residue
RUNX1 p.Arg346fs Likely pathogenic ★★★ 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

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-arg346pro (accessed [today's date]).

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