Is HBB p.Ser73fs (c.217dup) pathogenic?

HBB p.Ser73fs (c.217dup) is classified Pathogenic/Likely pathogenic in HBB (ClinVar, Multiple submitters, 13 submitters; last evaluated 2025-09-29). Very rare (popmax 0.00446%, eas); Associated with beta-thalassemia HBB/LCRB.

What condition is associated with HBB p.Ser73fs (c.217dup)?

HBB p.Ser73fs (c.217dup) is associated with beta-thalassemia HBB/LCRB, Heinz body anemia, dominant beta-thalassemia (ClinVar).

How common is HBB p.Ser73fs (c.217dup) in the general population?

HBB p.Ser73fs (c.217dup) is very rare (popmax 0.00446%, eas) (gnomAD).

HBB p.Ser73fs

c.217dup · rs33969853 · VCV15419

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

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 2 of 3
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.072	GERP 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,866 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000124% 2/1,614,140 alleles · very rare exomes 2/1,461,878 · genomes 0/152,262 · joint denominator

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.Ser73fs
Coding: c.217dup
MANE Select: NM_000518
dbSNP: rs33969853
Type: Duplication
Location: chr11:5226674 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 73: a functional site ((microbial infection) cleavage; by n.americanus apr-2); an α-helix; the globin domain

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.Ser73Ter Pathogenic same residue
HBB p.Ser73_Asp74delinsArgTyr Pathogenic same residue
HBB p.Ala11fs Pathogenic ★★ same condition
HBB p.Asn109fs Pathogenic ★★ same condition
HBB p.Asp22fs Likely pathogenic ★★ same condition
HBB p.Asp48fs Pathogenic ★★ same condition
HBB p.Glu44Ter Pathogenic ★★ same condition
HBB p.Leu29fs 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-ser73fs (accessed [today's date]).

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