Is RUNX2 p.Arg169Pro (c.506G>C) pathogenic?

RUNX2 p.Arg169Pro (c.506G>C) is classified Pathogenic in RUNX2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2002-11-01). AlphaMissense: likely pathogenic (0.9998); Absent from gnomAD v4.1; Associated with cleidocranial dysplasia 1.

What condition is associated with RUNX2 p.Arg169Pro (c.506G>C)?

RUNX2 p.Arg169Pro (c.506G>C) is associated with cleidocranial dysplasia 1 (ClinVar).

How common is RUNX2 p.Arg169Pro (c.506G>C) in the general population?

RUNX2 p.Arg169Pro (c.506G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RUNX2 p.Arg169Pro (c.506G>C)?

AlphaMissense predicts likely pathogenic (score 0.9998) — an in-silico prediction, not a clinical call.

RUNX2 p.Arg169Pro

c.506G>C · rs104893995 · VCV9306

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9998 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cleidocranial dysplasia 1

Computational evidence

Protein change
AlphaMissense	0.9998	likely pathogenic ✓ concordant with ClinVar · top 7% in RUNX2
REVEL	0.982	strongly pathogenic-leaning
SaProt	LLR -16.61	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, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 9,138 bp · p 0.00013 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

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: RUNX2
Protein: p.Arg169Pro
Coding: c.506G>C
MANE Select: NM_001024630
dbSNP: rs104893995
Type: single nucleotide variant
Location: chr6:45431945 (GRCh38)
Gene constraint: LOEUF 0.352 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 59.02 · 4 PDB
Residue 169: the runt domain; a UniProt-annotated variant site (in clcd1; decreased subcellular localization in the nucleus; decreased transactivation activity); a UniProt-annotated variant site (in clcd1)

Full RUNX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cleidocranial dysplasia 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RUNX2 p.Arg169Trp Pathogenic/Likely pathogenic ★★ same residue
RUNX2 p.Arg169Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
RUNX2 c.860-1G>A Likely pathogenic ★★ same condition
RUNX2 p.Arg190Gln Pathogenic ★★ same condition
RUNX2 p.Arg190Trp Pathogenic ★★ same condition
RUNX2 p.Arg193Gln Pathogenic/Likely pathogenic ★★ same condition
RUNX2 p.Arg193Ter Pathogenic ★★ same condition
RUNX2 p.Arg225Gln 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/runx2-p-arg169pro (accessed [today's date]).

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