Is SETBP1 p.Ser847Pro (c.2539T>C) pathogenic?

SETBP1 p.Ser847Pro (c.2539T>C) is classified Uncertain significance in SETBP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-31). AlphaMissense: ambiguous (0.5294); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SETBP1 p.Ser847Pro (c.2539T>C)?

SETBP1 p.Ser847Pro (c.2539T>C) is associated with Inborn genetic diseases (ClinVar).

How common is SETBP1 p.Ser847Pro (c.2539T>C) in the general population?

SETBP1 p.Ser847Pro (c.2539T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about SETBP1 p.Ser847Pro (c.2539T>C)?

AlphaMissense predicts ambiguous (score 0.5294) — an in-silico prediction, not a clinical call.

SETBP1 p.Ser847Pro

c.2539T>C · VCV4838959

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5294 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5294	ambiguous
REVEL	0.496	indeterminate
SaProt	LLR -6.74	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 339 bp · p 0.15 · regional, not allelic
Overall
CADD	27.4	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 8.47e-05% European (non-Finnish) · 1/1,179,984 alleles

Overall 6.2e-05% 1/1,613,724 alleles · very rare exomes 1/1,461,884 · genomes 0/151,840 · joint denominator

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: SETBP1
Protein: p.Ser847Pro
Coding: c.2539T>C
MANE Select: NM_015559
Type: single nucleotide variant
Location: chr18:44951879 (GRCh38)
Gene constraint: LOEUF 0.143 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.30

Full SETBP1 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

SETBP1 p.Ser847Cys Uncertain significance ★★ ⚠ same residue
SETBP1 p.Ser847Ala Uncertain significance ★ ⚠ same residue
SETBP1 p.Ser847Phe Uncertain significance ★ ⚠ same residue
SETBP1 p.Arg589Ter Pathogenic ★★ same condition
SETBP1 p.Gln809Ter Pathogenic ★★ same condition
SETBP1 p.Glu858Lys Pathogenic/Likely pathogenic ★★ ⚠ same condition
SETBP1 p.Ala1366Ser Uncertain significance ★★ ⚠ same condition
SETBP1 p.Ala436Val 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/setbp1-p-ser847pro (accessed [today's date]).

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