Is RUNX2 p.Pro30Ala (c.88C>G) pathogenic?

RUNX2 p.Pro30Ala (c.88C>G) is classified Uncertain significance in RUNX2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-30). AlphaMissense: ambiguous (0.4868); Very rare (popmax 0.00212%, nfe).

How common is RUNX2 p.Pro30Ala (c.88C>G) in the general population?

RUNX2 p.Pro30Ala (c.88C>G) is very rare (popmax 0.00212%, nfe) (gnomAD).

What do computational predictors say about RUNX2 p.Pro30Ala (c.88C>G)?

AlphaMissense predicts ambiguous (score 0.4868) — an in-silico prediction, not a clinical call.

RUNX2 p.Pro30Ala

c.88C>G · rs990671181 · VCV1303448

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4868 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00212%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4868	ambiguous
REVEL	0.396	indeterminate
SaProt	LLR -6.63	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.1	GERP 0.55, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 94 kb · p 0.5 · regional, not allelic
Overall
CADD	24.2	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 0.00212% European (non-Finnish) · 25/1,177,610 alleles

Filtering AF 0.00146% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00168% 27/1,607,148 alleles · very rare exomes 26/1,455,254 · genomes 1/151,894 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00212%	47,104
Remaining individualsnot grpmax-eligible	0.00161%	62,280
Finnishnot grpmax-eligible	0.00159%	62,946

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.Pro30Ala
Coding: c.88C>G
MANE Select: NM_001024630
dbSNP: rs990671181
Type: single nucleotide variant
Location: chr6:45422622 (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.Pro30Arg 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-pro30ala (accessed [today's date]).

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