Is SETBP1 p.Pro497= (c.1491G>A) pathogenic?

SETBP1 p.Pro497= (c.1491G>A) is classified Benign/Likely benign in SETBP1 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-01-28). Low-frequency (popmax 1.48%, afr); Associated with intellectual disability, autosomal dominant 29.

What condition is associated with SETBP1 p.Pro497= (c.1491G>A)?

SETBP1 p.Pro497= (c.1491G>A) is associated with intellectual disability, autosomal dominant 29, Schinzel-Giedion syndrome (ClinVar).

How common is SETBP1 p.Pro497= (c.1491G>A) in the general population?

SETBP1 p.Pro497= (c.1491G>A) is low-frequency (popmax 1.48%, afr) (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.

SETBP1 p.Pro497=

c.1491G>A · rs113053616 · VCV326740

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.48%, afr)

Conditions

intellectual disability, autosomal dominant 29

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.007	GERP -3.6, phastCons 0.09
Overall
CADD	6.073	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.48% African / African-American · 1,110/75,022 alleles

Filtering AF 1.41% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.38%

Overall 0.149% 2,411/1,614,110 alleles · low-frequency exomes 1,639/1,461,892 · genomes 772/152,218 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.48%	68
Finnishnot grpmax-eligible	1.27%	79
Ashkenazi Jewishnot grpmax-eligible	0.375%	267
Remaining individualsnot grpmax-eligible	0.205%	488
Admixed American	0.1%	1,000
Middle Eastern	0.066%	1,516
South Asian	0.0307%	3,253
European (non-Finnish)	0.0127%	7,867
East Asian	0.0111%	8,976

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.Pro497=
Coding: c.1491G>A
MANE Select: NM_015559
dbSNP: rs113053616
Type: single nucleotide variant
Location: chr18:44950831 (GRCh38)
Gene constraint: LOEUF 0.143 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.30
Residue 497: 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.Pro497Leu Benign/Likely benign ★★ 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
SETBP1 p.Asp868Asn Pathogenic ★★ ⚠ same condition
SETBP1 p.Asp868His Pathogenic/Likely 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-pro497 (accessed [today's date]).

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