Is SETBP1 p.Glu645Lys (c.1933G>A) pathogenic?

SETBP1 p.Glu645Lys (c.1933G>A) is classified Benign/Likely benign in SETBP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-09). AlphaMissense: likely benign (0.2909); Ultra-rare (popmax 0.012%, afr).

How common is SETBP1 p.Glu645Lys (c.1933G>A) in the general population?

SETBP1 p.Glu645Lys (c.1933G>A) is ultra-rare (popmax 0.012%, afr) (gnomAD).

What do computational predictors say about SETBP1 p.Glu645Lys (c.1933G>A)?

AlphaMissense predicts likely benign (score 0.2909) — an in-silico prediction, not a clinical call.

SETBP1 p.Glu645Lys

c.1933G>A · rs770454352 · VCV499149

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2909 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2909	likely benign
REVEL	0.36	indeterminate
SaProt	LLR -5.38	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 286 bp · p 0.45 · regional, not allelic
Overall
CADD	25.2	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 0.012% African / African-American · 9/74,918 alleles

Filtering AF 0.00624% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.0018% 29/1,613,608 alleles · ultra-rare exomes 25/1,461,438 · genomes 4/152,170 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,324
Admixed American	0.00667%	14,999
East Asian	0.00445%	22,447
Remaining individualsnot grpmax-eligible	0.0032%	31,242
European (non-Finnish)	0.00102%	98,337

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.Glu645Lys
Coding: c.1933G>A
MANE Select: NM_015559
dbSNP: rs770454352
Type: single nucleotide variant
Location: chr18:44951273 (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

Similar variants

SETBP1 p.Arg530Ter Pathogenic ★★ same type
SETBP1 p.Arg544Ter Pathogenic/Likely pathogenic ★★ same type
SETBP1 p.Arg589Ter Pathogenic ★★ same type
SETBP1 p.Arg625Ter Pathogenic ★★ same type
SETBP1 p.Arg626Ter Pathogenic ★★ same type
SETBP1 p.Arg889Ter Pathogenic ★★ same type
SETBP1 p.Asp868Asn Pathogenic ★★ ⚠ same type
SETBP1 p.Asp868His Pathogenic/Likely pathogenic ★★ ⚠ same type

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-glu645lys (accessed [today's date]).

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