Is SETBP1 p.Ala253Pro (c.757G>C) pathogenic?

SETBP1 p.Ala253Pro (c.757G>C) is classified Benign in SETBP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-22). AlphaMissense: likely benign (0.0955); Absent from gnomAD v4.1.

How common is SETBP1 p.Ala253Pro (c.757G>C) in the general population?

SETBP1 p.Ala253Pro (c.757G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SETBP1 p.Ala253Pro (c.757G>C)?

AlphaMissense predicts likely benign (score 0.0955) — an in-silico prediction, not a clinical call.

SETBP1 p.Ala253Pro

c.757G>C · rs149472556 · VCV2071745

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0955 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0955	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -6.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.8	GERP 2.7, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 249 kb · p 0.047 · regional, not allelic
Overall
CADD	21.2	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

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.Ala253Pro
Coding: c.757G>C
MANE Select: NM_015559
dbSNP: rs149472556
Type: single nucleotide variant
Location: chr18:44950097 (GRCh38)
Gene constraint: LOEUF 0.143 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.30
Residue 253: the 'disordered' region

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

Similar variants

SETBP1 p.Ala253Ser Uncertain significance ★★ ⚠ same residue
SETBP1 p.Ala253Thr Likely benign ★★ same residue
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

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-ala253pro (accessed [today's date]).

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