HBB p.Leu69=
c.207C>A · VCV3627289
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
very rare (popmax 0.00333%, 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 -13 | GERP -3.7 |
| Overall | ||
| CADD | 0.138 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00333%
Admixed American · 2/60,002 alleles
Filtering AF
0.000553%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.000207%
Overall
0.00031%
5/1,614,020 alleles · very rare
exomes 3/1,461,860 · genomes 2/152,160 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.00333% | 30,001 |
| African / African-American | 0.00133% | 74,984 |
| European (non-Finnish) | 0.000169% | 589,998 |
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
- HBB
- Protein
- p.Leu69=
- Coding
- c.207C>A
- MANE Select
- NM_000518
- Type
- single nucleotide variant
- Location
- chr11:5226685 (GRCh38)
- Gene constraint
- LOEUF 1.964 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 97.09 · 350 PDB
- Residue 69
- a UniProt-annotated variant site (in brisbane; o(2) affinity up); a UniProt-annotated variant site (in mizuho; unstable); an α-helix; the globin domain
Similar variants
- HBB p.Leu69Phe Pathogenic/Likely pathogenic ★★ ⚠ same residue
- HBB p.Leu69fs Likely pathogenic ★ same residue
- HBB c.316-146T>G Pathogenic ★★★ same type
- HBB c.316-197C>T Pathogenic ★★★ same type
- HBB c.92+5G>C Pathogenic ★★★ same type
- HBB c.-78A>C Pathogenic ★★★ same type
- HBB c.*111A>G Pathogenic ★★★ same type
- HBB p.Ala28Ser 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/hbb-p-leu69 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown