Is RUNX2 p.Phe197Ser (c.590T>C) pathogenic?

RUNX2 p.Phe197Ser (c.590T>C) is classified Pathogenic in RUNX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-29). AlphaMissense: likely pathogenic (1); Absent from gnomAD v4.1.

How common is RUNX2 p.Phe197Ser (c.590T>C) in the general population?

RUNX2 p.Phe197Ser (c.590T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RUNX2 p.Phe197Ser (c.590T>C)?

AlphaMissense predicts likely pathogenic (score 1) — an in-silico prediction, not a clinical call.

RUNX2 p.Phe197Ser

c.590T>C · rs2548593499 · VCV2734881

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

1 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	1	likely pathogenic ✓ concordant with ClinVar · top 7% in RUNX2
REVEL	0.979	strongly pathogenic-leaning
SaProt	LLR -15.98	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 7.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.05	constrained · MANE · 5,970 bp · p 1.9e-05 · regional, not allelic
Overall
CADD	28.8	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

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.Phe197Ser
Coding: c.590T>C
MANE Select: NM_001024630
dbSNP: rs2548593499
Type: single nucleotide variant
Location: chr6:45437956 (GRCh38)
Gene constraint: LOEUF 0.352 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 59.02 · 4 PDB
Residue 197: the runt domain; a UniProt-annotated variant site (in clcd1; decreased subcellular localization in the nucleus; decreased transactivation activity); a UniProt-annotated variant site (in clcd1; retains heterodimerization activity together with a trace potential for dna binding; retains a low but still substantial transactivation activity)

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

Similar variants

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
RUNX2 p.Arg193Ter 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-phe197ser (accessed [today's date]).

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