Is RUNX2 p.Pro402Ser (c.1204C>T) pathogenic?

RUNX2 p.Pro402Ser (c.1204C>T) is classified Uncertain significance in RUNX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-04-27). AlphaMissense: likely benign (0.1132); Absent from gnomAD v4.1; Associated with cleidocranial dysplasia 1.

What condition is associated with RUNX2 p.Pro402Ser (c.1204C>T)?

RUNX2 p.Pro402Ser (c.1204C>T) is associated with cleidocranial dysplasia 1 (ClinVar).

How common is RUNX2 p.Pro402Ser (c.1204C>T) in the general population?

RUNX2 p.Pro402Ser (c.1204C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RUNX2 p.Pro402Ser (c.1204C>T)?

AlphaMissense predicts likely benign (score 0.1132) — an in-silico prediction, not a clinical call.

RUNX2 p.Pro402Ser

c.1204C>T · rs1802417971 · VCV911358

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1132 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

cleidocranial dysplasia 1

Computational evidence

Protein change
AlphaMissense	0.1132	likely benign
REVEL	0.394	indeterminate
SaProt	LLR -6.00	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.8, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 55 kb · p 0.0088 · regional, not allelic
Overall
CADD	25.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RUNX2
Protein: p.Pro402Ser
Coding: c.1204C>T
MANE Select: NM_001024630
dbSNP: rs1802417971
Type: single nucleotide variant
Location: chr6:45546943 (GRCh38)
Gene constraint: LOEUF 0.352 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 59.02 · 4 PDB
Residue 402: a UniProt-annotated variant site (in clcd1; decreased subcellular localization in the nucleus; decreased transactivation activity); the 'interaction with kat6a' region; the 'interaction with kat6b' region; a UniProt-annotated variant site (in clcd1; unchanged subcellular localization; 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.Pro402Leu Uncertain significance ★ same residue
RUNX2 p.Pro402= 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

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-pro402ser (accessed [today's date]).

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