Is SETBP1 p.Pro1539Ser (c.4615C>T) pathogenic?

SETBP1 p.Pro1539Ser (c.4615C>T) is classified Likely pathogenic in SETBP1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-09-25). AlphaMissense: likely benign (0.1443); Very rare (popmax 0.00299%, eas); Associated with SETBP1-related disorder.

What condition is associated with SETBP1 p.Pro1539Ser (c.4615C>T)?

SETBP1 p.Pro1539Ser (c.4615C>T) is associated with SETBP1-related disorder (ClinVar).

How common is SETBP1 p.Pro1539Ser (c.4615C>T) in the general population?

SETBP1 p.Pro1539Ser (c.4615C>T) is very rare (popmax 0.00299%, eas) (gnomAD).

What do computational predictors say about SETBP1 p.Pro1539Ser (c.4615C>T)?

AlphaMissense predicts likely benign (score 0.1443) — an in-silico prediction, not a clinical call.

SETBP1 p.Pro1539Ser

c.4615C>T · VCV3354833

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1443 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00299%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

SETBP1-related disorder

Computational evidence

Protein change
AlphaMissense	0.1443	likely benign ⚠ discordant with ClinVar
REVEL	0.125	moderately benign-leaning
SaProt	LLR -11.73	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 3.9	GERP 1.2, phastCons 0.93
Regional constraint	o/e 0.94	unconstrained · MANE · 400 bp · p 0.42 · regional, not allelic
Overall
CADD	18.55	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 0.00299% East Asian · 1/33,424 alleles

Filtering AF 8.4e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.3e-05%

Overall 0.0004% 5/1,248,568 alleles · very rare exomes 5/1,102,864 · genomes 0/145,704 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00299%	33,424
Remaining individualsnot grpmax-eligible	0.00212%	47,264
European (non-Finnish)	0.000317%	315,488

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.Pro1539Ser
Coding: c.4615C>T
MANE Select: NM_015559
Type: single nucleotide variant
Location: chr18:45063522 (GRCh38)
Gene constraint: LOEUF 0.143 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.30
Residue 1539: 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

SETBP1-related disorder

Similar variants

SETBP1 p.Pro1539= Likely benign ★ same residue
SETBP1 p.Pro1539Leu Likely benign ★ ⚠ same residue
SETBP1 p.Arg544Ter Pathogenic/Likely pathogenic ★★ same condition
SETBP1 p.Arg626Ter Pathogenic ★★ same condition
SETBP1 p.Asp868Asn Pathogenic ★★ ⚠ same condition
SETBP1 p.Ser867Arg Pathogenic/Likely pathogenic ★★ ⚠ same condition
SETBP1 p.Lys664Glu Uncertain significance ★★ ⚠ same condition
SETBP1 p.Gln712Ter 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-pro1539ser (accessed [today's date]).

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