Is RUNX1 p.Arg166Pro (c.497G>C) pathogenic?

RUNX1 p.Arg166Pro (c.497G>C) is classified Uncertain significance in RUNX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-11-09). AlphaMissense: likely pathogenic (0.9996); Absent from gnomAD v4.1.

How common is RUNX1 p.Arg166Pro (c.497G>C) in the general population?

RUNX1 p.Arg166Pro (c.497G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RUNX1 p.Arg166Pro (c.497G>C)?

AlphaMissense predicts likely pathogenic (score 0.9996) — an in-silico prediction, not a clinical call.

RUNX1 p.Arg166Pro

c.497G>C · VCV4946213

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9996 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9996	likely pathogenic · top 9% in RUNX1
REVEL	0.938	strongly pathogenic-leaning
SaProt	LLR -13.99	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 52 kb · p 4.3e-12 · regional, not allelic
Overall
CADD	32.0	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 R139P vs ClinVar R166P) — 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.Arg166Pro
Coding: c.497G>C
MANE Select: NM_001754
Type: single nucleotide variant
Location: chr21:34880568 (GRCh38)
Gene constraint: LOEUF 0.633 · pLI 0.29 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.76 · 5 PDB
Residue 139 UniProt numbering: the runt domain; a binding site; the 'interaction with dna' region; a UniProt-annotated variant site (in fpdmm)

Full RUNX1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RUNX1 p.Arg166Gln Pathogenic ★★★ same residue
RUNX1 p.Arg166Ter Pathogenic ★★★ same residue
RUNX1 p.Arg166= Likely benign ★★★ same residue
RUNX1 p.Arg166Leu Likely pathogenic ★★ same residue
RUNX1 c.351+1G>A Pathogenic ★★★ same type
RUNX1 c.351+1G>C Likely pathogenic ★★★ same type
RUNX1 c.351+1G>T Pathogenic ★★★ same type
RUNX1 c.351+2T>A Likely pathogenic ★★★ same type

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-arg166pro (accessed [today's date]).

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