Is SETBP1 p.Val387Met (c.1159G>A) pathogenic?

SETBP1 p.Val387Met (c.1159G>A) is classified Benign/Likely benign in SETBP1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-19). AlphaMissense: likely benign (0.084); Ultra-rare (popmax 0.0329%, mid); Associated with Inborn genetic diseases.

What condition is associated with SETBP1 p.Val387Met (c.1159G>A)?

SETBP1 p.Val387Met (c.1159G>A) is associated with Inborn genetic diseases (ClinVar).

How common is SETBP1 p.Val387Met (c.1159G>A) in the general population?

SETBP1 p.Val387Met (c.1159G>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about SETBP1 p.Val387Met (c.1159G>A)?

AlphaMissense predicts likely benign (score 0.084) — an in-silico prediction, not a clinical call.

SETBP1 p.Val387Met

c.1159G>A · rs368829088 · VCV1620128

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.084 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.084	likely benign
REVEL	0.006	strongly benign-leaning
SaProt	LLR -7.59	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 0.37	GERP -5.4, phastCons 0.001
Regional constraint	o/e 1.09	unconstrained · MANE · 249 kb · p 0.047 · regional, not allelic
Overall
CADD	12.1	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 0.0329% Middle Eastern · 2/6,082 alleles

Filtering AF 0.0155% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0128%

Overall 0.00359% 58/1,613,794 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,041
African / African-American	0.024%	4,163
Admixed American	0.00667%	15,001
Remaining individualsnot grpmax-eligible	0.0048%	20,827
European (non-Finnish)	0.00246%	40,685
East Asian	0.00223%	44,870
South Asian	0.0011%	91,088

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.Val387Met
Coding: c.1159G>A
MANE Select: NM_015559
dbSNP: rs368829088
Type: single nucleotide variant
Location: chr18:44950499 (GRCh38)
Gene constraint: LOEUF 0.143 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.30
Residue 387: the 'disordered' region

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.Val387Leu 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
SETBP1 p.Arg143Gly 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-val387met (accessed [today's date]).

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