Is HBB p.Phe42fs (c.126_129del) pathogenic?

HBB p.Phe42fs (c.126129del) is classified Pathogenic/Likely pathogenic in HBB (ClinVar, Multiple submitters, 31 submitters; last evaluated 2026-02-01). Rare (popmax 0.12%, eas); Associated with beta-thalassemia HBB/LCRB.

What condition is associated with HBB p.Phe42fs (c.126_129del)?

HBB p.Phe42fs (c.126_129del) is associated with beta-thalassemia HBB/LCRB, Heinz body anemia, dominant beta-thalassemia (ClinVar).

How common is HBB p.Phe42fs (c.126_129del) in the general population?

HBB p.Phe42fs (c.126_129del) is rare (popmax 0.12%, eas) (gnomAD).

HBB p.Phe42fs

c.126_129del · rs80356821 · VCV15417

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 31 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.12%, 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 0.34	GERP 1
Overall
CADD	33.0	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 0.12% East Asian · 54/44,884 alleles

Filtering AF 0.0946% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0855%

Overall 0.00923% 149/1,614,116 alleles · rare exomes 134/1,461,876 · genomes 15/152,240 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.12%	831
South Asian	0.0955%	1,047
Remaining individualsnot grpmax-eligible	0.0128%	7,813

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.Phe42fs
Coding: c.126_129del
MANE Select: NM_000518
dbSNP: rs80356821
Type: Deletion
Location: chr11:5226763 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 42: a UniProt-annotated variant site (in mequon); a UniProt-annotated variant site (in bruxelles); 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 alpha thalassemia spectrum 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-phe42fs (accessed [today's date]).

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