Is HBB p.Lys9fs (c.25_26del) pathogenic?

HBB p.Lys9fs (c.2526del) is classified Pathogenic in HBB (ClinVar, Multiple submitters, 25 submitters; last evaluated 2026-06-01). Ultra-rare (popmax 0.0165%, mid); Associated with beta-thalassemia HBB/LCRB.

What condition is associated with HBB p.Lys9fs (c.25_26del)?

HBB p.Lys9fs (c.25_26del) is associated with beta-thalassemia HBB/LCRB, Heinz body anemia, dominant beta-thalassemia (ClinVar).

How common is HBB p.Lys9fs (c.25_26del) in the general population?

HBB p.Lys9fs (c.25_26del) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

HBB p.Lys9fs

c.25_26del · rs35497102 · VCV15413

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 25 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

beta-thalassemia HBB/LCRB

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 3
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.1	GERP -0.86, phastCons 0.49

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,056 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000868% 14/1,613,192 alleles · ultra-rare exomes 14/1,460,874 · genomes 0/152,318 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,056
Remaining individualsnot grpmax-eligible	0.008%	12,494
South Asian	0.0033%	30,348
European (non-Finnish)	0.000424%	235,831

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.Lys9fs
Coding: c.25_26del
MANE Select: NM_000518
dbSNP: rs35497102
Type: Deletion
Location: chr11:5226996 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 9: a functional site ((microbial infection) cleavage; by n.americanus apr-2); an α-helix; the globin domain; a UniProt-annotated variant site (in n-timone); a UniProt-annotated variant site (in j-luhe); a UniProt-annotated variant site (in rio grande)

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

Disease context

beta-thalassemia HBB/LCRB — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Heinz body anemia dominant beta-thalassemia sickle cell disease beta thalassemia hereditary persistence of fetal hemoglobin malaria, susceptibility to erythrocytosis, familial, 6

Similar variants

HBB c.315+2del Pathogenic/Likely pathogenic ★★ same condition
HBB c.93-22_95del Pathogenic ★★ same condition
HBB c.*110_*111del Pathogenic/Likely pathogenic ★★ same condition
HBB c.*110_*114del Pathogenic/Likely pathogenic ★★ same condition
HBB p.Glu23fs Pathogenic/Likely pathogenic ★★ same condition
HBB p.Glu7fs Pathogenic ★★ same condition
HBB p.Gly70fs Pathogenic/Likely pathogenic ★★ same condition
HBB p.Gly84fs Pathogenic ★★ 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/hbb-p-lys9fs (accessed [today's date]).

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