RUNX2 p.Pro295=
c.885G>A · rs554000247 · VCV1657214
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.0275%, sas)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -4.4 | GERP -5.9 |
| Overall | ||
| CADD | 4.588 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0275%
South Asian · 25/91,068 alleles
Filtering AF
0.019%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0163%
Overall
0.00248%
40/1,613,792 alleles · ultra-rare
exomes 31/1,461,764 · genomes 9/152,028 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.0275% | 3,643 |
| East Asian | 0.00669% | 14,957 |
| Admixed American | 0.00667% | 14,995 |
| African / African-American | 0.00267% | 37,469 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,498 |
| European (non-Finnish) | 0.000424% | 235,996 |
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.Pro295=
- Coding
- c.885G>A
- MANE Select
- NM_001024630
- dbSNP
- rs554000247
- Type
- single nucleotide variant
- Location
- chr6:45512271 (GRCh38)
- Gene constraint
- LOEUF 0.352 · pLI 1.00 (gnomAD)
- Structure
- AlphaFold pLDDT 59.02 · 4 PDB
- Residue 295
- a UniProt-annotated variant site (in clcd1; decreased subcellular localization in the nucleus; decreased transactivation activity); the 'disordered' region
Similar variants
- RUNX2 p.Pro295Leu Uncertain significance ★★ same residue
- RUNX2 p.Pro295fs Pathogenic ★ same residue
- RUNX2 c.860-1G>A Likely pathogenic ★★ same type
- RUNX2 c.860-1G>T Pathogenic/Likely pathogenic ★★ same type
- RUNX2 p.Ala362Val Pathogenic ★★ ⚠ same type
- RUNX2 p.Arg169Trp Pathogenic/Likely pathogenic ★★ same type
- RUNX2 p.Arg190Gln Pathogenic ★★ same type
- RUNX2 p.Arg190Trp 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/runx2-p-pro295 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown