Is RUNX2 p.Pro29Ser (c.85C>T) pathogenic?

RUNX2 p.Pro29Ser (c.85C>T) is classified Likely benign in RUNX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-16). AlphaMissense: likely pathogenic (0.6548); Very rare (popmax 0.00225%, eas).

How common is RUNX2 p.Pro29Ser (c.85C>T) in the general population?

RUNX2 p.Pro29Ser (c.85C>T) is very rare (popmax 0.00225%, eas) (gnomAD).

What do computational predictors say about RUNX2 p.Pro29Ser (c.85C>T)?

AlphaMissense predicts likely pathogenic (score 0.6548) — an in-silico prediction, not a clinical call.

RUNX2 p.Pro29Ser

c.85C>T · VCV3910542

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6548 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00225%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6548	likely pathogenic
REVEL	0.635	indeterminate
SaProt	LLR -5.47	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 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	25.1	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 0.00225% East Asian · 1/44,352 alleles

Filtering AF 0.00069% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00054%

Overall 0.00112% 18/1,607,086 alleles · very rare exomes 17/1,455,164 · genomes 1/151,922 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00321%	31,152
East Asiangrpmax	0.00225%	44,352
Finnishnot grpmax-eligible	0.00159%	62,930
European (non-Finnish)	0.00119%	84,111

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro29Ser
Coding: c.85C>T
MANE Select: NM_001024630
Type: single nucleotide variant
Location: chr6:45422619 (GRCh38)
Gene constraint: LOEUF 0.352 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 59.02 · 4 PDB
Residue 29: the 'disordered' region

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

Similar variants

RUNX2 p.Pro29Thr Uncertain significance ★ ⚠ same residue
RUNX2 p.Pro29= Likely benign ★ 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-pro29ser (accessed [today's date]).

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