Is SETBP1 p.Pro1529Ser (c.4585C>T) pathogenic?

SETBP1 p.Pro1529Ser (c.4585C>T) is classified Uncertain significance in SETBP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-08). AlphaMissense: likely benign (0.1355); Very rare (popmax 9.1e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SETBP1 p.Pro1529Ser (c.4585C>T)?

SETBP1 p.Pro1529Ser (c.4585C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SETBP1 p.Pro1529Ser (c.4585C>T) in the general population?

SETBP1 p.Pro1529Ser (c.4585C>T) is very rare (popmax 9.1e-05%, nfe) (gnomAD).

What do computational predictors say about SETBP1 p.Pro1529Ser (c.4585C>T)?

AlphaMissense predicts likely benign (score 0.1355) — an in-silico prediction, not a clinical call.

SETBP1 p.Pro1529Ser

c.4585C>T · rs2511370048 · VCV3160570

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1355 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 9.1e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1355	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -11.07	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 1.7, phastCons 0.91
Regional constraint	o/e 0.94	unconstrained · MANE · 400 bp · p 0.42 · regional, not allelic
Overall
CADD	17.39	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 9.1e-05% European (non-Finnish) · 1/1,099,090 alleles

Overall 7.74e-05% 1/1,292,126 alleles · very rare

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.Pro1529Ser
Coding: c.4585C>T
MANE Select: NM_015559
dbSNP: rs2511370048
Type: single nucleotide variant
Location: chr18:45063492 (GRCh38)
Gene constraint: LOEUF 0.143 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.30
Residue 1529: the 'disordered' region; the '3 x 8 aa tandem repeats of p-p-l-p-p-p-p-p' region

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.Pro1529= Likely benign ★ 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
SETBP1 p.Ala745Asp Uncertain significance ★★ ⚠ same condition
SETBP1 p.Arg143Gly 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-pro1529ser (accessed [today's date]).

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