# NM_000518.5(HBB):c.17_18del (p.Pro6fs)

https://sugi.bio/variant/hbb-p-pro6fs

## Summary

**HBB p.Pro6fs (c.17_18del)** 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.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs34889882 · 24 submitters · 8 linked conditions · ultra-rare (popmax 0.033%, mid)

> **Built without this gene's context.** ClinVar files this variant under an overlapping gene, so its own gene's record set does not contain it and this page is assembled from the variant alone. Gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up — absent from this page, not from the data.

## For patients & families {#patients}

This is a change in the HBB gene that is considered disease-causing, submitted by 24 submitters, and is linked to beta-thalassemia HBB/LCRB.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Clinical trials | 9 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024933/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [HBB](https://sugi.bio/atlas/gene/HBB/) |
| Protein change (HGVS p.) | p.Pro6fs |
| Coding change (HGVS c.) | c.17_18del |
| MANE Select transcript | [NM_000518](https://www.ncbi.nlm.nih.gov/nuccore/NM_000518) |
| dbSNP | [rs34889882](https://www.ncbi.nlm.nih.gov/snp/rs34889882/) |
| Variant type | Deletion |
| Location | chr11:5227004-5227005 (GRCh38) |
| ClinVar | [VCV15422](https://www.ncbi.nlm.nih.gov/clinvar/variation/15422/) |

**All HGVS expressions:** `LRG_1232:g.5067_5068del`, `LRG_1232t1:c.17_18del`, `NC_000011.10:g.5227004_5227005del`, `NC_000011.9:g.5248234_5248235del`, `NG_000007.3:g.70611_70612del`, `NG_042296.1:g.535_536del`, `NG_046672.1:g.4939_4940del`, `NG_059281.1:g.5067_5068del`, `NM_000518.5:c.17_18del`, `NM_000518.5:c.17_18delCT`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 1.673, GERP 1.87, phastCons 0.002 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. For a truncating variant the loss-of-function impact is position-dependent — C-terminal / last-exon truncations may escape nonsense-mediated decay. *Descriptive; not an applied PVS1 code.*
- CADD: **PHRED 21.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **0.033%** (mid) · FAF95 0.0228% · FAF99 0.0196% · 2/6,054 in the highest group · 38/1,611,036 alleles overall — ultra-rare (popmax 0.033%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.033% | 3,027 |
| South Asian | 0.0319% | 3,139 |
| European (non-Finnish) | 0.000595% | 168,170 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-10-28.

**Submitter consensus:** unanimous (24/24 Pathogenic).

**Submission history:** 23 submissions (1989–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Pathogenic | criteria provided, single submitter | clinical testing | 2022-11-03 |
| Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Pathogenic | criteria provided, single submitter | curation | 2024-02-01 |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-04-27 |
| Revvity Omics, Revvity | Pathogenic | criteria provided, single submitter | clinical testing | 2024-04-04 |
| Natera, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2025-10-28 |
| 3billion | Pathogenic | criteria provided, single submitter | clinical testing | 2025-07-08 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2017-06-06 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 1989-01-01 |
| Clinical Genetics and Genomics, Karolinska University Hospital | Pathogenic | criteria provided, single submitter | clinical testing | 2016-01-05 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | Pathogenic | criteria provided, single submitter | clinical testing | 2023-05-22 |
| PreventionGenetics, part of Exact Sciences | Pathogenic | no assertion criteria provided | clinical testing | 2024-02-11 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Pathogenic | criteria provided, single submitter | clinical testing | 2025-07-07 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2025-10-01 |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing |  |
| The ITHANET community portal, The Cyprus Institute of Neurology and Genetics | Pathogenic | no assertion criteria provided | curation | 2019-11-25 |
| Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-04 |
| Genome-Nilou Lab | Pathogenic | criteria provided, single submitter | clinical testing | 2021-07-22 |
| MOLECULAR BIOLOGY AND HUMAN GENETICS DIVISION, THE UNIVERSITY OF BURDWAN | Pathogenic | no assertion criteria provided | clinical testing | 2024-05-07 |
| Institute of Human Genetics, University of Leipzig Medical Center | Pathogenic | criteria provided, single submitter | clinical testing | 2024-12-27 |
| Counsyl | Pathogenic | no assertion criteria provided | clinical testing | 2018-05-08 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-12-30 |
| Institute of Immunology and Genetics Kaiserslautern | Pathogenic | criteria provided, single submitter | clinical testing | 2025-10-20 |
| Variantyx, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-03 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-03-01 |

## Associated conditions {#conditions}

[beta-thalassemia HBB/LCRB](https://sugi.bio/atlas/disease/beta-thalassemia-hbb-lcrb/), [Heinz body anemia](https://sugi.bio/atlas/disease/heinz-body-anemia/), [dominant beta-thalassemia](https://sugi.bio/atlas/disease/dominant-beta-thalassemia/), [sickle cell disease](https://sugi.bio/atlas/disease/sickle-cell-disease/), [beta thalassemia](https://sugi.bio/atlas/disease/beta-thalassemia/), [hereditary persistence of fetal hemoglobin](https://sugi.bio/atlas/disease/hereditary-persistence-of-fetal-hemoglobin/), [malaria, susceptibility to](https://sugi.bio/atlas/disease/malaria-susceptibility-to/), [erythrocytosis, familial, 6](https://sugi.bio/atlas/disease/erythrocytosis-familial-6/).

**Reported phenotype names (ClinVar):** Beta-thalassemia HBB/LCRB, Beta zero thalassemia, not provided, beta Thalassemia, Hb SS disease, HBB-related disorder, Dominant beta-thalassemia, Erythrocytosis, familial, 6, Heinz body anemia, Hereditary persistence of fetal hemoglobin.

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 15422). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*