Is HBB p.Leu76fs (c.226del) pathogenic?

HBB p.Leu76fs (c.226del) is classified Pathogenic/Likely pathogenic in HBB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-25). No gnomAD frequency available for this variant; Associated with beta thalassemia.

What condition is associated with HBB p.Leu76fs (c.226del)?

HBB p.Leu76fs (c.226del) is associated with beta thalassemia (ClinVar).

How common is HBB p.Leu76fs (c.226del) in the general population?

HBB p.Leu76fs (c.226del) is no gnomAD frequency available for this variant (gnomAD).

HBB p.Leu76fs

c.226del · rs34218908 · VCV495983

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

beta thalassemia

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 2 of 3
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 8.8	GERP 1.9, phastCons 0.98

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: HBB
Protein: p.Leu76fs
Coding: c.226del
MANE Select: NM_000518
dbSNP: rs34218908
Type: Deletion
Location: chr11:5226666 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 76: a UniProt-annotated variant site (in atlanta; unstable); a UniProt-annotated variant site (in pasadena; o(2) affinity up; unstable); a functional site ((microbial infection) cleavage; by n.americanus apr-2); the globin domain

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

Disease context

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

Similar variants

HBB p.Leu76= Uncertain significance same residue
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

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-leu76fs (accessed [today's date]).

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