Is RUNX1 p.Pro382Arg (c.1145C>G) pathogenic?

RUNX1 p.Pro382Arg (c.1145C>G) is classified Uncertain significance in RUNX1 (ClinVar, Expert panel, 2 submitters; last evaluated 2024-10-29). AlphaMissense: likely pathogenic (0.955); Absent from gnomAD v4.1; Associated with hereditary thrombocytopenia and hematologic cancer predisposition syndrome.

What condition is associated with RUNX1 p.Pro382Arg (c.1145C>G)?

RUNX1 p.Pro382Arg (c.1145C>G) 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.Pro382Arg (c.1145C>G) in the general population?

RUNX1 p.Pro382Arg (c.1145C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RUNX1 p.Pro382Arg (c.1145C>G)?

AlphaMissense predicts likely pathogenic (score 0.955) — an in-silico prediction, not a clinical call.

RUNX1 p.Pro382Arg

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.1145C>G · rs2145876238 · VCV1397177

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.955 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 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 PP3

Curation rationale (ClinGen, verbatim)

NM_001754.5(RUNX1):c.1145C>G (p.Pro382Arg) is a missense variant which is absent from all population databases, including gnomAD v2.1.1 and gnomAD v3.1.2, both of which provide coverage of at least 20x for the RUNX1 gene at this genomic position (PM2_supporting). This missense variant has a REVEL score >0.88 (0.942) (PP3). To our knowledge, this variant has not been reported before, and there are no other pathogenic or likely pathogenic amino acid changes affecting the same residue. 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, PP3.

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

Computational evidence

Protein change
AlphaMissense	0.955	likely pathogenic
REVEL	0.942	strongly pathogenic-leaning
SaProt	LLR -11.71	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 42 kb · p 0.0085 · regional, not allelic
Overall
CADD	26.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P355R vs ClinVar P382R) — 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.Pro382Arg
Coding: c.1145C>G
MANE Select: NM_001754
dbSNP: rs2145876238
Type: single nucleotide variant
Location: chr21:34792433 (GRCh38)
Gene constraint: LOEUF 0.633 · pLI 0.29 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.76 · 5 PDB
Residue 355 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.Pro382Leu Uncertain significance ★★★ ⚠ same residue
RUNX1 p.Pro382= Likely benign ★ 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
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-pro382arg (accessed [today's date]).

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