Is SETBP1 p.Ser686Arg (c.2056A>C) pathogenic?

SETBP1 p.Ser686Arg (c.2056A>C) is classified Benign in SETBP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-29). AlphaMissense: likely pathogenic (0.846); Very rare (popmax 0.0011%, sas).

How common is SETBP1 p.Ser686Arg (c.2056A>C) in the general population?

SETBP1 p.Ser686Arg (c.2056A>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about SETBP1 p.Ser686Arg (c.2056A>C)?

AlphaMissense predicts likely pathogenic (score 0.846) — an in-silico prediction, not a clinical call.

SETBP1 p.Ser686Arg

c.2056A>C · rs376810199 · VCV2698292

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.846 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.846	likely pathogenic
REVEL	0.273	benign-leaning
SaProt	LLR -7.81	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 286 bp · p 0.45 · regional, not allelic
Overall
CADD	25.0	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 0.0011% South Asian · 1/91,080 alleles

Overall 6.2e-05% 1/1,614,192 alleles · very rare exomes 1/1,461,868 · genomes 0/152,324 · 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.Ser686Arg
Coding: c.2056A>C
MANE Select: NM_015559
dbSNP: rs376810199
Type: single nucleotide variant
Location: chr18:44951396 (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.Ser686Cys 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-ser686arg (accessed [today's date]).

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