Is SETBP1 p.Ser1296Arg (c.3888T>A) pathogenic?

SETBP1 p.Ser1296Arg (c.3888T>A) is classified Benign in SETBP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-24). AlphaMissense: ambiguous (0.439); Very rare (popmax 0.000593%, nfe).

How common is SETBP1 p.Ser1296Arg (c.3888T>A) in the general population?

SETBP1 p.Ser1296Arg (c.3888T>A) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about SETBP1 p.Ser1296Arg (c.3888T>A)?

AlphaMissense predicts ambiguous (score 0.439) — an in-silico prediction, not a clinical call.

SETBP1 p.Ser1296Arg

c.3888T>A · rs1263083665 · VCV2696778

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.439 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.439	ambiguous
REVEL	0.256	benign-leaning
SaProt	LLR -7.17	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP -1.8, phastCons 0.002
Regional constraint	o/e 1.07	unconstrained · MANE · 110 kb · p 0.16 · regional, not allelic
Overall
CADD	14.28	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 0.000593% European (non-Finnish) · 7/1,179,924 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,613,420 alleles · very rare exomes 6/1,461,852 · genomes 1/151,568 · joint denominator

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.Ser1296Arg
Coding: c.3888T>A
MANE Select: NM_015559
dbSNP: rs1263083665
Type: single nucleotide variant
Location: chr18:44953228 (GRCh38)
Gene constraint: LOEUF 0.143 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.30
Residue 1296: the 'disordered' region

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

Similar variants

SETBP1 p.Ser1296Asn Uncertain significance ★ ⚠ 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
SETBP1 p.Asp868Asn 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-ser1296arg (accessed [today's date]).

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