Is SETBP1 p.Pro1545Ser (c.4633C>T) pathogenic?

SETBP1 p.Pro1545Ser (c.4633C>T) is classified Conflicting classifications of pathogenicity in SETBP1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-07-08). AlphaMissense: likely benign (0.1048); Very rare (popmax 0.00152%, afr); Associated with Inborn genetic diseases.

What condition is associated with SETBP1 p.Pro1545Ser (c.4633C>T)?

SETBP1 p.Pro1545Ser (c.4633C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SETBP1 p.Pro1545Ser (c.4633C>T) in the general population?

SETBP1 p.Pro1545Ser (c.4633C>T) is very rare (popmax 0.00152%, afr) (gnomAD).

What do computational predictors say about SETBP1 p.Pro1545Ser (c.4633C>T)?

AlphaMissense predicts likely benign (score 0.1048) — an in-silico prediction, not a clinical call.

SETBP1 p.Pro1545Ser

c.4633C>T · rs753471483 · VCV2391193

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1048 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00152%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1048	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -7.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 1.1, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 400 bp · p 0.42 · regional, not allelic
Overall
CADD	15.82	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 0.00152% African / African-American · 1/65,600 alleles

Filtering AF 9.3e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.3e-05%

Overall 0.000442% 6/1,357,816 alleles · very rare exomes 5/1,214,530 · genomes 1/143,286 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00152%	65,600
South Asian	0.00137%	72,842
European (non-Finnish)	0.000398%	251,140

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.Pro1545Ser
Coding: c.4633C>T
MANE Select: NM_015559
dbSNP: rs753471483
Type: single nucleotide variant
Location: chr18:45063540 (GRCh38)
Gene constraint: LOEUF 0.143 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.30
Residue 1545: the 'disordered' 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.Pro1545His Uncertain significance ★ ⚠ same residue
SETBP1 p.Pro1545Ala 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

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-pro1545ser (accessed [today's date]).

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