Is RUNX2 p.Pro30Arg (c.89C>G) pathogenic?

RUNX2 p.Pro30Arg (c.89C>G) is classified Uncertain significance in RUNX2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-03-01). AlphaMissense: likely pathogenic (0.9152); Very rare (popmax 0.00535%, afr).

How common is RUNX2 p.Pro30Arg (c.89C>G) in the general population?

RUNX2 p.Pro30Arg (c.89C>G) is very rare (popmax 0.00535%, afr) (gnomAD).

What do computational predictors say about RUNX2 p.Pro30Arg (c.89C>G)?

AlphaMissense predicts likely pathogenic (score 0.9152) — an in-silico prediction, not a clinical call.

RUNX2 p.Pro30Arg

c.89C>G · VCV4692361

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9152 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00535%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9152	likely pathogenic
REVEL	0.553	indeterminate
SaProt	LLR -7.92	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.4	GERP 1.5, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 94 kb · p 0.5 · regional, not allelic
Overall
CADD	24.4	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

Grpmax group 0.00535% African / African-American · 4/74,740 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000622% 10/1,606,964 alleles · very rare exomes 7/1,454,960 · genomes 3/152,004 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00535%	18,685
Admixed American	0.0017%	58,818
Remaining individualsnot grpmax-eligible	0.00161%	62,290
Finnishnot grpmax-eligible	0.00159%	62,940
European (non-Finnish)	0.000255%	392,502

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.Pro30Arg
Coding: c.89C>G
MANE Select: NM_001024630
Type: single nucleotide variant
Location: chr6:45422623 (GRCh38)
Gene constraint: LOEUF 0.352 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 59.02 · 4 PDB
Residue 30: the 'disordered' region

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

Similar variants

RUNX2 p.Pro30Ala Uncertain significance ★★ same residue
RUNX2 p.Pro30His Uncertain significance ★ ⚠ 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-pro30arg (accessed [today's date]).

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