SETD1B p.Ala376=
c.1128C>T · rs781386265 · VCV2643426
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0333%, amr)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 3.1 | GERP 0.48, phastCons 1 |
| Overall | ||
| CADD | 10.82 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0333%
Admixed American · 17/51,004 alleles
Filtering AF
0.0212%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0174%
Overall
0.00729%
113/1,550,268 alleles · ultra-rare
exomes 95/1,397,984 · genomes 18/152,284 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.0333% | 3,000 |
| European (non-Finnish) | 0.00793% | 12,604 |
| African / African-American | 0.0041% | 24,383 |
| Ashkenazi Jewishnot grpmax-eligible | 0.00349% | 28,644 |
| Remaining individualsnot grpmax-eligible | 0.00166% | 60,088 |
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
- SETD1B
- Protein
- p.Ala376=
- Coding
- c.1128C>T
- MANE Select
- NM_001353345
- dbSNP
- rs781386265
- Type
- single nucleotide variant
- Location
- chr12:121810073 (GRCh38)
- Gene constraint
- LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 46.43 · 4 PDB
- Residue 376
- the 'disordered' region
Similar variants
- SETD1B p.Ala376Val Uncertain significance ★ ⚠ same residue
- SETD1B p.Arg1329Ter Pathogenic ★★ same type
- SETD1B p.Arg1703Ter Pathogenic/Likely pathogenic ★★ same type
- SETD1B p.Arg1748Cys Pathogenic/Likely pathogenic ★★ same type
- SETD1B p.Arg1792Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
- SETD1B p.Arg1825Trp Likely pathogenic ★★ same type
- SETD1B p.Arg1902Cys Pathogenic/Likely pathogenic ★★ same type
- SETD1B p.Gln780Ter Pathogenic/Likely 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/setd1b-p-ala376 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown