Is HBB p.Glu7fs (c.20del) pathogenic?

HBB p.Glu7fs (c.20del) is classified Pathogenic in HBB (ClinVar, Multiple submitters, 18 submitters; last evaluated 2026-01-21). Very rare (popmax 0.00267%, afr); Associated with beta-thalassemia HBB/LCRB.

What condition is associated with HBB p.Glu7fs (c.20del)?

HBB p.Glu7fs (c.20del) is associated with beta-thalassemia HBB/LCRB, Heinz body anemia, dominant beta-thalassemia (ClinVar).

How common is HBB p.Glu7fs (c.20del) in the general population?

HBB p.Glu7fs (c.20del) is very rare (popmax 0.00267%, afr) (gnomAD).

HBB p.Glu7fs

c.20del · rs63749819 · VCV15418

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 18 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

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 -20	GERP -3.7
Overall
CADD	17.66	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,872 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000831%

Overall 0.00143% 23/1,611,916 alleles · very rare exomes 20/1,459,706 · genomes 3/152,210 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,209
African / African-Americangrpmax	0.00267%	37,436
European (non-Finnish)	0.00161%	62,003

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Glu7fs
Coding: c.20del
MANE Select: NM_000518
dbSNP: rs63749819
Type: Deletion
Location: chr11:5227002 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 7: an α-helix; the globin domain; a UniProt-annotated variant site (in g-makassar); a UniProt-annotated variant site (in hb c; confers resistance to severe malaria); a UniProt-annotated variant site (in machida); a UniProt-annotated variant site (in skca; hb s; at heterozygosity confers resistance to malaria)

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 p.Glu7Lys Pathogenic/Likely pathogenic ★★ ⚠ same residue
HBB p.Glu7Val Pathogenic ★★ ⚠ same residue
HBB p.Glu7Met Likely pathogenic ★ same residue
HBB p.Glu7Ter Pathogenic 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

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-glu7fs (accessed [today's date]).

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