Is SETBP1 p.Val489Ala (c.1466T>C) pathogenic?

SETBP1 p.Val489Ala (c.1466T>C) is classified Uncertain significance in SETBP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-10). AlphaMissense: likely benign (0.0952); Absent from gnomAD v4.1; Associated with SETBP1-related disorder.

What condition is associated with SETBP1 p.Val489Ala (c.1466T>C)?

SETBP1 p.Val489Ala (c.1466T>C) is associated with SETBP1-related disorder (ClinVar).

How common is SETBP1 p.Val489Ala (c.1466T>C) in the general population?

SETBP1 p.Val489Ala (c.1466T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SETBP1 p.Val489Ala (c.1466T>C)?

AlphaMissense predicts likely benign (score 0.0952) — an in-silico prediction, not a clinical call.

SETBP1 p.Val489Ala

c.1466T>C · rs2511467759 · VCV2635425

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0952 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

SETBP1-related disorder

Computational evidence

Protein change
AlphaMissense	0.0952	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -6.39	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 2.4	GERP -0.81, phastCons 0.95
Regional constraint	o/e 1.09	unconstrained · MANE · 249 kb · p 0.047 · regional, not allelic
Overall
CADD	10.89	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SETBP1
Protein: p.Val489Ala
Coding: c.1466T>C
MANE Select: NM_015559
dbSNP: rs2511467759
Type: single nucleotide variant
Location: chr18:44950806 (GRCh38)
Gene constraint: LOEUF 0.143 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.30
Residue 489: the 'disordered' region

Full SETBP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

SETBP1-related disorder

Similar variants

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
SETBP1 p.Pro855Ser Likely pathogenic ★ ⚠ same condition
SETBP1 p.Ser477Ter 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-val489ala (accessed [today's date]).

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