Is HBB p.Pro6fs (c.17_18del) pathogenic?

HBB p.Pro6fs (c.1718del) is classified Pathogenic in HBB (ClinVar, Multiple submitters, 24 submitters; last evaluated 2025-10-28). Ultra-rare (popmax 0.033%, mid); Associated with beta-thalassemia HBB/LCRB.

What condition is associated with HBB p.Pro6fs (c.17_18del)?

HBB p.Pro6fs (c.17_18del) is associated with beta-thalassemia HBB/LCRB, Heinz body anemia, dominant beta-thalassemia (ClinVar).

How common is HBB p.Pro6fs (c.17_18del) in the general population?

HBB p.Pro6fs (c.17_18del) is ultra-rare (popmax 0.033%, mid) (gnomAD).

HBB p.Pro6fs

c.17_18del · rs34889882 · VCV15422

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 24 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Conditions

beta-thalassemia HBB/LCRB

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 1.7	GERP 1.9, phastCons 0.002
Overall
CADD	21.0	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 0.033% Middle Eastern · 2/6,054 alleles

Filtering AF 0.0228% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0196%

Overall 0.00236% 38/1,611,036 alleles · ultra-rare exomes 32/1,458,702 · genomes 6/152,334 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,027
South Asian	0.0319%	3,139
European (non-Finnish)	0.000595%	168,170

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.Pro6fs
Coding: c.17_18del
MANE Select: NM_000518
dbSNP: rs34889882
Type: Deletion
Location: chr11:5227004 (GRCh38)

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

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-pro6fs (accessed [today's date]).

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