Is SETBP1 p.Pro37His (c.110C>A) pathogenic?

SETBP1 p.Pro37His (c.110C>A) is classified Benign in SETBP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-14). AlphaMissense: likely benign (0.123); Very rare (popmax 0.005%, amr).

How common is SETBP1 p.Pro37His (c.110C>A) in the general population?

SETBP1 p.Pro37His (c.110C>A) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about SETBP1 p.Pro37His (c.110C>A)?

AlphaMissense predicts likely benign (score 0.123) — an in-silico prediction, not a clinical call.

SETBP1 p.Pro37His

c.110C>A · rs747388683 · VCV1430819

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.123 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.123	likely benign
REVEL	0.127	moderately benign-leaning
SaProt	LLR -7.84	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 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 232 bp · p 0.68 · regional, not allelic
Overall
CADD	22.3	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 0.005% Admixed American · 3/59,944 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000186% 3/1,612,908 alleles · very rare exomes 3/1,460,710 · genomes 0/152,198 · 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.Pro37His
Coding: c.110C>A
MANE Select: NM_015559
dbSNP: rs747388683
Type: single nucleotide variant
Location: chr18:44701456 (GRCh38)
Gene constraint: LOEUF 0.143 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.30
Residue 37: the 'disordered' region

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

Similar variants

SETBP1 p.Pro37Leu Likely benign ★★ same residue
SETBP1 p.Pro37Ser Uncertain significance ★ ⚠ same residue
SETBP1 p.Pro37= 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

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-pro37his (accessed [today's date]).

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