Is RUNX2 p.Pro485Ser (c.1453C>T) pathogenic?

RUNX2 p.Pro485Ser (c.1453C>T) is classified Uncertain significance in RUNX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-16). AlphaMissense: likely benign (0.1093); Very rare (popmax 0.00833%, amr).

How common is RUNX2 p.Pro485Ser (c.1453C>T) in the general population?

RUNX2 p.Pro485Ser (c.1453C>T) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about RUNX2 p.Pro485Ser (c.1453C>T)?

AlphaMissense predicts likely benign (score 0.1093) — an in-silico prediction, not a clinical call.

RUNX2 p.Pro485Ser

c.1453C>T · rs1421970328 · VCV3015674

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1093 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1093	likely benign
REVEL	0.236	benign-leaning
SaProt	LLR -5.34	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 55 kb · p 0.0088 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00833% Admixed American · 5/60,024 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00206%

Overall 0.00031% 5/1,614,166 alleles · very rare exomes 5/1,461,878 · genomes 0/152,288 · 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.Pro485Ser
Coding: c.1453C>T
MANE Select: NM_001024630
dbSNP: rs1421970328
Type: single nucleotide variant
Location: chr6:45547192 (GRCh38)
Gene constraint: LOEUF 0.352 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 59.02 · 4 PDB
Residue 485: a UniProt-annotated variant site (in clcd1; decreased subcellular localization in the nucleus; decreased transactivation activity); a UniProt-annotated variant site (in clcd1; unchanged subcellular localization; decreased transactivation activity); the 'disordered' region; a UniProt-annotated variant site (in clcd1; decreased protein stability; decreased transactivation activity; decreased osteoblast differentiation)

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

Similar variants

RUNX2 p.Pro485Thr 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
RUNX2 p.Arg193Gln Pathogenic/Likely 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-pro485ser (accessed [today's date]).

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