Is HBB p.Trp16fs (c.45dup) pathogenic?

HBB p.Trp16fs (c.45dup) is classified Pathogenic in HBB (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-07-27). Very rare (popmax 0.00223%, eas); Associated with erythrocytosis, familial, 6.

What condition is associated with HBB p.Trp16fs (c.45dup)?

HBB p.Trp16fs (c.45dup) is associated with erythrocytosis, familial, 6, Heinz body anemia, dominant beta-thalassemia (ClinVar).

How common is HBB p.Trp16fs (c.45dup) in the general population?

HBB p.Trp16fs (c.45dup) is very rare (popmax 0.00223%, eas) (gnomAD).

HBB p.Trp16fs

c.45dup · rs35383398 · VCV15426

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

erythrocytosis, familial, 6

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 5.2	GERP 1.9, phastCons 0.39

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,876 alleles

Overall 6.2e-05% 1/1,613,616 alleles · very rare exomes 1/1,461,322 · genomes 0/152,294 · 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.Trp16fs
Coding: c.45dup
MANE Select: NM_000518
dbSNP: rs35383398
Type: Duplication
Location: chr11:5226976 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 16: an α-helix; the globin domain; a UniProt-annotated variant site (in randwick; unstable); a UniProt-annotated variant site (in belfast; o(2) affinity up; unstable)

Full HBB gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

erythrocytosis, familial, 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Heinz body anemia dominant beta-thalassemia sickle cell disease beta-thalassemia HBB/LCRB beta thalassemia hereditary persistence of fetal hemoglobin malaria, susceptibility to hemoglobinopathy

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-trp16fs (accessed [today's date]).

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