RUNX2 p.Val221=
c.663A>G · rs115763613 · VCV357092
Benign/Likely benign
Multiple submitters
Classification
Benign/Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 6 submitters
gnomAD v4.1
Rare
low-frequency (popmax 1.47%, afr)
Conditions
1
cleidocranial dysplasia 1
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 5.8 | GERP 0.93, phastCons 1 |
| Overall | ||
| CADD | 8.277 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
1.47%
African / African-American · 1,102/75,002 alleles
Filtering AF
1.4%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 1.37%
Overall
0.0829%
1,336/1,611,610 alleles · low-frequency
exomes 634/1,459,246 · genomes 702/152,364 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 1.47% | 68 |
| Admixed American | 0.173% | 577 |
| Middle Eastern | 0.149% | 673 |
| Remaining individualsnot grpmax-eligible | 0.141% | 709 |
| South Asian | 0.00659% | 15,176 |
| European (non-Finnish) | 0.00229% | 43,621 |
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
- RUNX2
- Protein
- p.Val221=
- Coding
- c.663A>G
- MANE Select
- NM_001024630
- dbSNP
- rs115763613
- Type
- single nucleotide variant
- Location
- chr6:45438029 (GRCh38)
- Gene constraint
- LOEUF 0.352 · pLI 1.00 (gnomAD)
- Structure
- AlphaFold pLDDT 59.02 · 4 PDB
- Residue 221
- the runt domain; a UniProt-annotated variant site (in clcd1; decreased subcellular localization in the nucleus; decreased transactivation activity)
Similar variants
- RUNX2 c.860-1G>A Likely pathogenic ★★ same condition
- RUNX2 p.Arg169Trp Pathogenic/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
- RUNX2 p.Arg225Trp 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-val221 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown