Is RUNX2 p.Arg100Ser (c.298C>A) pathogenic?

RUNX2 p.Arg100Ser (c.298C>A) is classified Uncertain significance in RUNX2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-19). AlphaMissense: likely pathogenic (0.9953); Very rare (popmax 0.00225%, eas); Associated with cleidocranial dysplasia 1.

What condition is associated with RUNX2 p.Arg100Ser (c.298C>A)?

RUNX2 p.Arg100Ser (c.298C>A) is associated with cleidocranial dysplasia 1 (ClinVar).

How common is RUNX2 p.Arg100Ser (c.298C>A) in the general population?

RUNX2 p.Arg100Ser (c.298C>A) is very rare (popmax 0.00225%, eas) (gnomAD).

What do computational predictors say about RUNX2 p.Arg100Ser (c.298C>A)?

AlphaMissense predicts likely pathogenic (score 0.9953) — an in-silico prediction, not a clinical call.

RUNX2 p.Arg100Ser

c.298C>A · rs754711247 · VCV911154

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9953 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00225%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cleidocranial dysplasia 1

Computational evidence

Protein change
AlphaMissense	0.9953	likely pathogenic
REVEL	0.941	strongly pathogenic-leaning
SaProt	LLR -11.99	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 7.2	GERP 1.5, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 94 kb · p 0.5 · regional, not allelic
Overall
CADD	28.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00225% East Asian · 1/44,442 alleles

Overall 6.22e-05% 1/1,608,196 alleles · very rare exomes 1/1,456,156 · genomes 0/152,040 · joint denominator

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.Arg100Ser
Coding: c.298C>A
MANE Select: NM_001024630
dbSNP: rs754711247
Type: single nucleotide variant
Location: chr6:45422832 (GRCh38)
Gene constraint: LOEUF 0.352 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 59.02 · 4 PDB
Residue 100: a UniProt-annotated variant site (in clcd1; decreased subcellular localization in the nucleus; decreased transactivation activity)

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.Arg100= Likely benign ★ same residue
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

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-arg100ser (accessed [today's date]).

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