Is SETBP1 p.Ala75Val (c.224C>T) pathogenic?

SETBP1 p.Ala75Val (c.224C>T) is classified Conflicting classifications of pathogenicity in SETBP1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-04-07). AlphaMissense: likely benign (0.2712); Very rare (popmax 0.0011%, sas); Associated with Inborn genetic diseases.

What condition is associated with SETBP1 p.Ala75Val (c.224C>T)?

SETBP1 p.Ala75Val (c.224C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SETBP1 p.Ala75Val (c.224C>T) in the general population?

SETBP1 p.Ala75Val (c.224C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about SETBP1 p.Ala75Val (c.224C>T)?

AlphaMissense predicts likely benign (score 0.2712) — an in-silico prediction, not a clinical call.

SETBP1 p.Ala75Val

c.224C>T · rs770368733 · VCV3004563

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2712 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2712	likely benign
REVEL	0.278	benign-leaning
SaProt	LLR -6.42	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 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	25.3	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 0.0011% South Asian · 1/91,070 alleles

Overall 0.000124% 2/1,614,096 alleles · very rare exomes 2/1,461,882 · genomes 0/152,214 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,070
European (non-Finnish)	8.47e-05%	1,180,026

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.Ala75Val
Coding: c.224C>T
MANE Select: NM_015559
dbSNP: rs770368733
Type: single nucleotide variant
Location: chr18:44701570 (GRCh38)
Gene constraint: LOEUF 0.143 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.30
Residue 75: 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.Ala75Glu Uncertain significance ★ ⚠ same residue
SETBP1 p.Ala75= Likely 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-ala75val (accessed [today's date]).

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