Is HBB p.Pro126fs (c.375dup) pathogenic?

HBB p.Pro126fs (c.375dup) is classified Likely pathogenic in HBB (ClinVar, Single submitter, 2 submitters; last evaluated 2024-04-18). Very rare (popmax 8.48e-05%, nfe); Associated with beta thalassemia.

What condition is associated with HBB p.Pro126fs (c.375dup)?

HBB p.Pro126fs (c.375dup) is associated with beta thalassemia (ClinVar).

How common is HBB p.Pro126fs (c.375dup) in the general population?

HBB p.Pro126fs (c.375dup) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

HBB p.Pro126fs

c.375dup · rs281864544 · VCV869284

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

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	escapes	premature termination codon in the last exon (3 of 3) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -7.6	GERP -3.2

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,878 alleles

Overall 6.2e-05% 1/1,614,016 alleles · very rare exomes 1/1,461,706 · genomes 0/152,310 · 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.Pro126fs
Coding: c.375dup
MANE Select: NM_000518
dbSNP: rs281864544
Type: Duplication
Location: chr11:5225666 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 126: an α-helix; 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.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
HBB p.Leu97fs Pathogenic ★★ same condition
HBB p.Ser73fs 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-pro126fs (accessed [today's date]).

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