Is RUNX2 p.Pro304Ser (c.910C>T) pathogenic?

RUNX2 p.Pro304Ser (c.910C>T) is classified Uncertain significance in RUNX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-18). AlphaMissense: likely benign (0.1521); Very rare (popmax 0.00401%, afr); Associated with Inborn genetic diseases.

What condition is associated with RUNX2 p.Pro304Ser (c.910C>T)?

RUNX2 p.Pro304Ser (c.910C>T) is associated with Inborn genetic diseases (ClinVar).

How common is RUNX2 p.Pro304Ser (c.910C>T) in the general population?

RUNX2 p.Pro304Ser (c.910C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about RUNX2 p.Pro304Ser (c.910C>T)?

AlphaMissense predicts likely benign (score 0.1521) — an in-silico prediction, not a clinical call.

RUNX2 p.Pro304Ser

c.910C>T · VCV3315804

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1521 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1521	likely benign
REVEL	0.456	indeterminate
SaProt	LLR -5.87	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 1.8, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 55 kb · p 0.0088 · regional, not allelic
Overall
CADD	24.3	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 0.00401% African / African-American · 3/74,888 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.00031% 5/1,613,990 alleles · very rare exomes 2/1,461,836 · genomes 3/152,154 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,963
European (non-Finnish)	0.000169%	590,009

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.Pro304Ser
Coding: c.910C>T
MANE Select: NM_001024630
Type: single nucleotide variant
Location: chr6:45512296 (GRCh38)
Gene constraint: LOEUF 0.352 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 59.02 · 4 PDB
Residue 304: a UniProt-annotated variant site (in clcd1; decreased subcellular localization in the nucleus; decreased transactivation activity); the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RUNX2 c.1022-67T>A Uncertain significance ★★ same condition
RUNX2 p.Ala414Thr Uncertain significance ★★ ⚠ same condition
RUNX2 p.Arg251His Uncertain significance ★★ ⚠ same condition
RUNX2 p.Arg338His Uncertain significance ★★ same condition
RUNX2 p.Arg92Gln Uncertain significance ★★ ⚠ same condition
RUNX2 p.Gln301Arg Uncertain significance ★★ same condition
RUNX2 p.Gly479Val Uncertain significance ★★ ⚠ same condition
RUNX2 p.Leu367Val Uncertain significance ★★ ⚠ 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-pro304ser (accessed [today's date]).

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