Is SETBP1 p.Pro855Thr (c.2563C>A) pathogenic?

SETBP1 p.Pro855Thr (c.2563C>A) is classified Conflicting classifications of pathogenicity in SETBP1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-07-28). AlphaMissense: likely pathogenic (0.9766); Absent from gnomAD v4.1; Associated with intellectual disability, autosomal dominant 29.

What condition is associated with SETBP1 p.Pro855Thr (c.2563C>A)?

SETBP1 p.Pro855Thr (c.2563C>A) is associated with intellectual disability, autosomal dominant 29, Schinzel-Giedion syndrome (ClinVar).

How common is SETBP1 p.Pro855Thr (c.2563C>A) in the general population?

SETBP1 p.Pro855Thr (c.2563C>A) is absent from gnomAD v4.1 (gnomAD).

How is Non-specific syndromic intellectual disability inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about SETBP1 p.Pro855Thr (c.2563C>A)?

AlphaMissense predicts likely pathogenic (score 0.9766) — an in-silico prediction, not a clinical call.

SETBP1 p.Pro855Thr

c.2563C>A · rs2145105580 · VCV1315372

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9766 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

intellectual disability, autosomal dominant 29

Computational evidence

Protein change
AlphaMissense	0.9766	likely pathogenic · top 8% in SETBP1
REVEL	0.57	indeterminate
SaProt	LLR -6.50	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.9, phastCons 1
Regional constraint	o/e 0.27	constrained · MANE · 100 bp · p 7.6e-07 · regional, not allelic
Overall
CADD	25.6	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.Pro855Thr
Coding: c.2563C>A
MANE Select: NM_015559
dbSNP: rs2145105580
Type: single nucleotide variant
Location: chr18:44951903 (GRCh38)
Gene constraint: LOEUF 0.143 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.30
Residue 855: the 'disordered' region

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

Disease context

intellectual disability, autosomal dominant 29 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Schinzel-Giedion syndrome

For Non-specific syndromic intellectual disability (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Childhood, Infancy

Similar variants

SETBP1 p.Pro855Leu Likely pathogenic ★ ⚠ same residue
SETBP1 p.Pro855Ser Likely pathogenic ★ ⚠ same residue
SETBP1 p.Pro855His Uncertain significance ★ ⚠ same residue
SETBP1 p.Arg530Ter Pathogenic ★★ same condition
SETBP1 p.Arg544Ter Pathogenic/Likely pathogenic ★★ same condition
SETBP1 p.Arg589Ter Pathogenic ★★ same condition
SETBP1 p.Arg625Ter Pathogenic ★★ same condition
SETBP1 p.Arg626Ter 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-pro855thr (accessed [today's date]).

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