Is SETBP1 p.Ser869Arg (c.2607C>G) pathogenic?

SETBP1 p.Ser869Arg (c.2607C>G) is classified Pathogenic/Likely pathogenic in SETBP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-10). AlphaMissense: likely pathogenic (0.9999); Absent from gnomAD v4.1; Associated with Schinzel-Giedion syndrome.

What condition is associated with SETBP1 p.Ser869Arg (c.2607C>G)?

SETBP1 p.Ser869Arg (c.2607C>G) is associated with Schinzel-Giedion syndrome (ClinVar).

How common is SETBP1 p.Ser869Arg (c.2607C>G) in the general population?

SETBP1 p.Ser869Arg (c.2607C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SETBP1 p.Ser869Arg (c.2607C>G)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

SETBP1 p.Ser869Arg

c.2607C>G · rs74499808 · VCV2573005

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Schinzel-Giedion syndrome

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic ✓ concordant with ClinVar · top 1% in SETBP1
REVEL	0.637	indeterminate
SaProt	LLR -10.13	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.4	GERP -5.7
Regional constraint	o/e 0.27	constrained · MANE · 100 bp · p 7.6e-07 · regional, not allelic
Overall
CADD	14.28	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: SETBP1
Protein: p.Ser869Arg
Coding: c.2607C>G
MANE Select: NM_015559
dbSNP: rs74499808
Type: single nucleotide variant
Location: chr18:44951947 (GRCh38)
Gene constraint: LOEUF 0.143 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.30
Residue 869: the 'disordered' region; a UniProt-annotated variant site (in mds and myeloid malignancies); a UniProt-annotated variant site (in myeloid malignancies)

Full SETBP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Schinzel-Giedion syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SETBP1 p.Ser869= Benign/Likely benign ★★ same residue
SETBP1 p.Ser869Asn Pathogenic ★ same residue
SETBP1 p.Arg589Ter Pathogenic ★★ same condition
SETBP1 p.Arg625Ter Pathogenic ★★ same condition
SETBP1 p.Arg626Ter Pathogenic ★★ same condition
SETBP1 p.Asp868Asn Pathogenic ★★ ⚠ same condition
SETBP1 p.Asp868His Pathogenic/Likely pathogenic ★★ ⚠ same condition
SETBP1 p.Glu858Lys Pathogenic/Likely 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/setbp1-p-ser869arg (accessed [today's date]).

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