Is SETBP1 p.Ala1111Asp (c.3332C>A) pathogenic?

SETBP1 p.Ala1111Asp (c.3332C>A) is classified Benign/Likely benign in SETBP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-08). AlphaMissense: ambiguous (0.3893); Very rare (popmax 0.00364%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SETBP1 p.Ala1111Asp (c.3332C>A)?

SETBP1 p.Ala1111Asp (c.3332C>A) is associated with Inborn genetic diseases (ClinVar).

How common is SETBP1 p.Ala1111Asp (c.3332C>A) in the general population?

SETBP1 p.Ala1111Asp (c.3332C>A) is very rare (popmax 0.00364%, nfe) (gnomAD).

What do computational predictors say about SETBP1 p.Ala1111Asp (c.3332C>A)?

AlphaMissense predicts ambiguous (score 0.3893) — an in-silico prediction, not a clinical call.

SETBP1 p.Ala1111Asp

c.3332C>A · rs776403982 · VCV2152802

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3893 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00364%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3893	ambiguous
REVEL	0.123	moderately benign-leaning
SaProt	LLR -5.95	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 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 697 bp · p 0.0093 · regional, not allelic
Overall
CADD	23.4	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 0.00364% European (non-Finnish) · 43/1,180,034 alleles

Filtering AF 0.00275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00244%

Overall 0.00279% 45/1,613,990 alleles · very rare exomes 44/1,461,884 · genomes 1/152,106 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00364%	27,443
Remaining individualsnot grpmax-eligible	0.0032%	31,244

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.Ala1111Asp
Coding: c.3332C>A
MANE Select: NM_015559
dbSNP: rs776403982
Type: single nucleotide variant
Location: chr18:44952672 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SETBP1 p.Ala1111= Likely benign ★ same residue
SETBP1 p.Ala1111Val Benign ★ same residue
SETBP1 p.Arg589Ter Pathogenic ★★ same condition
SETBP1 p.Gln809Ter Pathogenic ★★ same condition
SETBP1 p.Glu858Lys Pathogenic/Likely pathogenic ★★ ⚠ same condition
SETBP1 p.Ala1366Ser Uncertain significance ★★ ⚠ same condition
SETBP1 p.Ala436Val Uncertain significance ★★ ⚠ same condition
SETBP1 p.Ala745Asp Uncertain significance ★★ ⚠ 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-ala1111asp (accessed [today's date]).

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