Is HBB p.Val127fs (c.380_396del) pathogenic?

HBB p.Val127fs (c.380396del) is classified Pathogenic in HBB (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-04-08). Very rare (popmax 0.0011%, sas); Associated with beta thalassemia.

What condition is associated with HBB p.Val127fs (c.380_396del)?

HBB p.Val127fs (c.380_396del) is associated with beta thalassemia (ClinVar).

How common is HBB p.Val127fs (c.380_396del) in the general population?

HBB p.Val127fs (c.380_396del) is very rare (popmax 0.0011%, sas) (gnomAD).

HBB p.Val127fs

c.380_396del · rs750606223 · VCV1459872

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

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 7.7	GERP 1.9, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,080 alleles

Overall 6.2e-05% 1/1,614,096 alleles · very rare exomes 1/1,461,812 · genomes 0/152,284 · 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.Val127fs
Coding: c.380_396del
MANE Select: NM_000518
dbSNP: rs750606223
Type: Deletion
Location: chr11:5225646 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 127: a UniProt-annotated variant site (in beirut); a UniProt-annotated variant site (in hofu; unstable); a UniProt-annotated variant site (in b-thal; dhonburi/neapolis; unstable); 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.Val127Gly Uncertain significance ★★★ ⚠ same residue
HBB p.Val127Glu Conflicting classifications of pathogenicity ★ ⚠ 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

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-val127fs (accessed [today's date]).

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